Elevated transaminases after blood transfusion?

This sparks HCV immediately in my mind. However, there may be other possibilities too.

What can you deduce from elevated transaminases if you only know that the healthy adult patient received blood transfusion in Africa?

Safety Assessment including Current and Emerging Issues in Toxicologic Pathology

Hepatocellular Leakage Enzymes

Serum ALT is the most useful non-invasive test for detection of hepatocellular injury in most laboratory animal species, although it is not truly liver specific in any. Muscle injury will also lead to increased serum ALT activity, although generally those increases are not as pronounced as can occur from liver injury. Leakage of hepatocellular ALT will elevate serum activity within hours, with a peak 1–2 days after a toxic insult. Serum half-life in dogs is about 60 hours. The range of serum ALT in young dogs (4–7 months) is quite narrow and allows small increases to be detected. As animals age, the range of serum ALT within a group increases and small elevations are harder to detect, especially when small numbers of animals are used in a study.

Serum AST activity tends to parallel ALT activity in liver injury, although ALT is considered a more specific and sensitive biomarker than AST for hepatocellular injury in rats, dogs, and non-human primates (NHPs). When both aminotransferase activities are increased as a consequence of hepatotoxicity the magnitude of the ALT increase is usually greater than that of AST due, in part, to the cytosolic location and longer half-life of ALT and the greater proportion of AST in mitochondria.

Evaluation of both ALT and AST can help distinguish liver injury from muscle injury, since the magnitude of AST elevation is greater than that of ALT following muscle injury. Serum half-life of AST is about 12 hours in dogs, therefore following acute injury, serum activity of AST will return to normal more quickly than serum ALT activity. The magnitude of serum ALT and AST elevations correlates with the number of affected hepatocytes and does not indicate the severity or potential reversibility of the injury.

Decreases in serum activity of ALT and AST may occasionally be seen in non-clinical toxicology studies however, an etiology for these changes is often undetermined. Decreases may indicate decreased production or release, a loss of functional hepatic mass, inhibition of enzyme activity (in vivo or in the test system), or inhibition of the coenzyme pyridoxal 5′phosphate (P5P, the active form of vitamin B6). Decreased ALT activity has been occasionally observed with concurrent hepatic microsomal enzyme (P4501A1) induction in the rat, although slightly increased ALT more commonly is associated with microsomal induction.

Serum sorbitol dehydrogenase (SDH) and glutamate dehydrogenase (GDH) are liver-specific enzymes present in the cytosol and mitochondria, respectively. Evaluations of these enzymes are useful in species where ALT activity is low or less specific, such as swine, cattle, sheep, guinea pigs, woodchucks, and some strains of rats, or in situations where ALT is not effective in detecting hepatic injury despite evidence of hepatic necrosis.

A review of sixty-one 13-week rat toxicity studies demonstrated a positive association between increased ALT, SDH, and histopathology changes in the liver. Presence or absence of increased SDH alone had greater positive and negative predictive values than ALT alone, but elevations in both enzymes reliably predicted liver histopathology by 2–3 weeks following initiation of administration of a hepatotoxicant. However, liver histopathology lesions without increased ALT or SDH occurred in 23% of the studies, demonstrating that serum biochemistry and histopathology are not always linked.

GDH has been reported to have high sensitivity for detection of injury, high tissue specificity, prolonged persistence in blood following injury, and lower susceptibility for inhibition or induction in rats. SDH and GDH are not often used in human medicine to assess liver injury, so alterations that may be seen in a non-clinical setting will not likely be followed into the clinic.

Postoperative liver enzyme abnormalities are related to staged restorative proctocolectomy

Background: Transient homeostatic derangements are found after major abdominal and pelvic surgery. We observed elevated liver function tests (LFTs) after restorative proctocolectomy (RPC). This study was undertaken to determine the etiology and implications of elevated LFTs before RPC and postoperatively.

Methods: One hundred and thirty-four RPC-patients were prospectively evaluated for LFT abnormalities. Patients were assigned to two groups: hand-sewn ileal-reservoir after mucosoproctocolectomy (n=83) or stapled anastomosis (n=9), both with loop ileostomy and stapled anastomosis without loop ileostomy (n=42). Serum alanine-aminotransferase (ALAT) and alkaline phosphatases (ALP) were assessed preoperatively, 1-10 weeks postoperatively before loop ileostomy closure and 1-10 weeks after ileostomy closure. These findings were correlated with anesthesia time, transfused blood volume, perioperatively administered drugs, and length of the diverted bowel while having a loop ileostomy.

Results: A large number of patients showed initial elevated serum ALAT and ALP levels, suggesting liver cell damage. There was a substantial and significant increase in ALAT and ALP in the first postoperative week. The values normalized within 2 weeks for the group without loop ileostomy, but not until after loop ileostomy closure in first group. A significant correlation as to length of diverted bowel (<0.05) while having a loop ileostomy was noted. When the length of diverted bowel was more than 105 cm, liver enzymes were higher than baseline levels (p<0.05) until after closure.

Conclusions: Patients may develop elevated LFTs after RPC however, its etiology and significance remains unclear. A loop ileostomy with RPC seemed to delay the normalization. Consideration of further diagnostic imaging may be indicated to exclude other liver pathology such as sclerosing cholangitis.

Materials and Methods


Two groups of volunteers at Sanquin, the Dutch national blood service collection center (Zwolle, the Netherlands), were followed prospectively after whole blood donation. For this observational study, one group consisted of 23 non-diabetic blood donating volunteers, the other group consisted of 21 blood donating volunteers with type 2 diabetes. Both groups were matched in age and gender and fulfilled the eligibility criteria for donating whole blood in the Netherlands (Sanquin, Amsterdam, the Netherlands). The volunteers with type 2 diabetes were selected from the Sanquin blood donor database on the basis of their use of diabetes medication. Subsequently, age and gender matched non-diabetic volunteers were selected to reduce bias. The study (NL47160.075.13) was approved by Sanquin’s institutional review board and the Medical Ethics Review Committee (Isala Hospital, Zwolle, the Netherlands). Written informed consent was obtained from all volunteers.


Blood donors were followed prospectively for nine weeks. In the first week they voluntarily donated 475 mL of whole blood and two extra test tubes were collected for determining HbA1c and confounding factors: urea, creatinine, gamma-glutamyl transpeptidase, aspartate transaminase, alanine transaminase, C-reactive protein (CRP) and ferritin. In addition, hematological parameters were determined (hemoglobin, hematocrit, mean corpuscular volume, reticulocytes and reticulocyte hemoglobin content). In the subsequent weeks each blood donor visited the center on the same weekday as the weekday of whole blood donation for collecting two test tubes for determining HbA1c, CRP, ferritin and hematological parameters. Vitamin B12 and folic acid were determined predonation and 4 weeks post donation to monitor vitamin status which could affect erythropoiesis. Predonation (baseline) characteristics of HbA1c, ferritin, hemoglobin, vitamin B12 and folic acid are listed in Table 1.

Test tubes were labeled anonymously before being sent to the laboratory and were analyzed within three hours at the clinical chemical laboratory of the Isala hospital (Zwolle, the Netherlands). Samples for HbA1c were stored at -80°C and analyzed at the end of the study in one run for each donor to prevent bias. All volunteers had donated previously without any problems. Each week volunteers were asked whether there was any change in diet, medication, health status, infection or other particulars. The study was performed from January until March 2015.

Laboratory measurements

HbA1c analysis was performed at the European Reference Laboratory for Glycohemoglobin (Zwolle, the Netherlands). HbA1c measurements were performed in duplicate at the end of the study in a single run for each blood donor. HbA1c was measured using 3 different secondary reference measurement procedures (SRMP) certified by the International Federation of Clinical Chemistry and Laboratory Medicine and the National Glycohemoglobin Standardization Program (IFCC and NGSP): Roche Tina-quant HbA1c Gen.2 on Integra 800, immunoassay, IFCC and NGSP certified (Roche Diagnostics, Almere, the Netherlands) Premier Hb9210, affinity chromatography HPLC, IFCC and NGSP certified (Trinity Biotech, Bray, Ireland) Tosoh G8, cation-exchange HPLC, IFCC certified (Tosoh Bioscience, Griesheim, Germany). The SRMP’s have documented good results in the IFCC and NGSP monitoring programs and were calibrated using the IFCC secondary reference material with assigned IFCC and derived NGSP values [6–8].

The analytical coefficients of variation (CVa) for the individual analyzers used in this study were determined: Tosoh G8 CVa 0.69% (IFCC) and CVa 0.41% (DCCT) Premier Hb9210 CVa 0.73% (IFCC) and CVa 0.43% (DCCT) Tina-quant CVa 1.91% (IFCC) and CVa 1.11% (DCCT). 9 Three different SRMP’s were used to show the possible variations between the different analyzers. Hematological parameters were measured using a XN-9000 hematology analyzer (Sysmex, Etten-Leur, the Netherlands). All other parameters were measured using a Cobas 8000 analyzer (Roche Diagnostics, Almere, the Netherlands).

Data analysis and statistics

Data analysis was performed using Graphpad Prism 6 (GraphPad Software, California, USA). Comparisons between different groups were performed using the two-tailed Mann-Whitney test. P values <0.05 were considered significant. Statistical dependence between two variables was assessed using Spearman’s rho. The reference change value ( ), used for the assessment of the significance of differences in serial HbA1c results from individual subjects, was calculated using the analytical coefficient of variation and the within-subject biological variation (CVw) of each HbA1c assay method mentioned above [9]. The RCV and % HbA1c change or reduction from baseline used throughout the article are based on SI units (mmol/mol) unless stated otherwise. For the non-blood donating group [9] a two-tailed RCV was calculated using a Z value of 1.96 (P < 0.05) for interpretation of the change in HbA1c. For the non-diabetic group and the group with type 2 diabetes donating whole blood, an one-tailed RCV was calculated using a Z value of 1.65 (P < 0.05) for interpretation of the expected reduction in HbA1c [10]. Two volunteers missed one out of 8 follow-up appointments, both appeared on the appointment on the last scheduled visit. Percentage HbA1c decrease was calculated omitting these missing data points, possibly resulting in an underestimation of the maximum HbA1c reduction in two volunteers.

Diseases Spread by Blood Transfusion

The pool of donor blood is screened very carefully for infectious disease and is very safe. However, there is a very small chance of contracting life-threatening diseases from donor blood. There is also a small chance of contracting other illnesses or infections from a blood transfusion.

The National Heart, Lung and Blood Institute estimates that there is approximately a 1 in 2,000,000 chance of contracting Hepatitis C or HIV from a blood transfusion. There is a 1 in 205,000 chance of contracting Hepatitis B.

While it is essential that you are aware of the risks of transfusions, it is also important to keep these odds in perspective. For example, you are four times more likely to be killed by an asteroid than you are to contract HIV or Hepatitis C through a transfusion.

Veronica - Yes they are the same Grandparents - Grandmas mother had Alzheimer's and so we have been vigilant to those type of signs to look for. Other then forgetting a restaurants name or something on her grocery list (that we all do) she has been pretty clear.

She seems to be doing better but we have had a pretty rough ride. After the hospital she still had some pretty bad edema in her hands and feet - no indication of pneumonia or anything like that. Her hands got better but gravity took over and the swelling moved to her feet. Saturday night I went up to take her meds and found that her legs had sprung leaks. I had never seen anything of the sort and so with the help of the nursing staff we got TED hose on her and this morning they looked SOOOO much better. now it will be blood pressure issues. And my kids are sick. I just cant catch a break!

If it's any consolation my Mom was totally confused after having gall bladder removed at 88 yrs old, they had to keep her in the hospital for 6 days which is an outpatient procedure for most..

Give her time, she'll come around.

Haha, a wake up call at 2 a.m. IS pretty funny. We need a laugh once in awhile. sorry if it is at the expense of your sleep.

But, this is GREAT news, it sounds like she's a fighter, a "tough old bird" as they used to call my mom! That may make all the difference in her recovery. Keep up your positive support.

Dance - thank u 4 responding. It seems so many who post don't come back and answer the most trivial questions that would help us help more.

You see, by captain posting his (always very honest & descriptive) comment about colonoscopies, we have ferreted out even more reasons for what maybe (hopefully) only confusion at this stage.

We now know that your grandmother had sedation/anesthesia twice in a short period of time. Just google "elders (or seniors) anesthesia surgery" and you will find plenty of information about how late life surgery/anesthetic can contribute to or bring on dementia. As in your g/m's case, this was life-saving rather than elective surgery so you don't always have a choice. If they had it removed her ascending colon because of a mass, she may have had a bowel blockage anyway which would either lead to a necessary surgery or death.

Now we come to the matter of the transfusions. These are just averages, round numbers, given for purposes of comparison. An average woman will have 6 to 7 pints of blood in her body (blood volume is based on body mass, not height) but a 110 pound woman will have only about 5 pints. So g/m had one pint before surgery and two pints afterward. This is more than half of her blood volume. Basic biology or physiology 101 will tell you that the hemoglobin (iron) in the blood is what carries oxygen to all the cells of the body. Oxygen is critical for the brain. Once the anemia is discovered, it takes a reasonable amount of infusion time to drip in the new blood. So there is a period of time where there could be ongoing clinical anemia, with less oxygen being supplied to the brain. No one can say for sure (unless later brain scans so indicate that part of her brain may have been starved for oxygen).

I'm not saying this DID happen I'm saying it's a POSSIBILITY. Several years ago, the brother of one of my dearest friends had a heart attack and survived. But, in the process of getting him going again, part of his brain was oxygen starved for a short amount of time. He was later diagnosed with "infarct dementia", as the lack of blood to his brain during the heart attack had allowed certain brain cells to die. His dementia was a stable type, in other words he didn't continue deteriorating as a dementia patient often does. The damage that was done was isolated to the cells that died during the oxygen starvation. He lost short term memory but other than that he was a very congenial guy, even though he needed 24/7 supervision.

You can question the doctor and if it does turn out to be the case that this MAY be the problem, your g/m still may have it in her power to recover some or all of her prior self. The body has incredible and remarkable healing powers on its own. As I said before, diligent observation/care and fortified nutrition are about the only things from the outside that could help her body heal. Your energy age by her side, belief in the healing power of the mind and body, energy healing or prayer if you are into that, can all day off aid & assistance to her in regaining her wellness.

Please keep us informed on her progress! And take care of yourself in the process!!

What does having Anti-kell antibodies in the blood indicate?

Q: I am a 51 years old female. I recently had an ankle surgery. I was cross typed and matched in case of blood transfusion. I just received a card in the mail from the hospital which states "Transfusion Restriction, This patient has the following clinically significant antibodies, Anti-Kell". What does this mean? I suffer from macrocytic anaemia but have had no transfusions for the last 11 years.

A:Our red blood cells (and some tissues) have got chemical substances called antigens on their surface and the ability to form these antigens is governed by genes inherited from parents. These antigens may be proteins, carbohydrates or other complex chemicals. The presence of these antigens (and their antibodies) has given rise to blood group systems and they play a role in blood transfusion and tissue typing. Currently about 30 different blood group systems are known in humans but the ones of clincal significance are the ABO system, Rh system, Kell, MNS, Lewis etc. The importance of blood group systems lies in transfusion and transplant medicine as we can receive blood (or organ) from only an individual whose blood group matches ours. In case of mismatch, the body's immune system recognises the 'foreign' antigen and fights it leading to disease states. Thus, blood group matching is done so that compatible blood (or tissue) is selected.

The Kell antigen system (or the Kell-Cellano system) was named after the family of the antibody producer Mrs. Kellacher. It is one of the major antigenic systems in human red blood cells and is important in transfusion medicine because the antibodies can cause severe reactions to transfusion of incompatible blood and hemolytic disease in newborn infants (HDN). It consists of over 20 different antigens (KEL1 to KEL24), which are coded by a gene complex present on chromosome 7. The k antigen (Cellano or K2) is far more common than K antigen (Kell or K1). Approximately 9% of the population has the K1 RBC phenotype and antibodies to K1 are developed in about 5% of persons receiving a single unit of incompatible blood. The reason is related to frequent transfusion-alloimmunization by Kell antigen and the low frequency of the K:1 gene among fathers. Kell hemolysis is severe in about half of cases.

Kell allo-immunization in women can be caused by pregnancy with a Kell-positive baby or, more commonly, following transfusion with Kell-positive blood i.e. individuals lacking a specific Kell antigen may develop antibodies against Kell antigens when transfused with blood containing that antigen or being exposed to red cells bearing that antigen. Subsequent blood transfusions may be marked by destruction of the new cells by these antibodies. People without Kell antigens (K0), must be transfused with blood from donors who are also K0 to prevent hemolysis. Autoimmune hemolytic anemia (AIHA) occurs when the body produces an antibody against a blood group antigen on its own red blood cells. The antibodies lead to destruction of the red blood cells with resulting anemia. The majority of cases of Kell sensitization are secondary to incompatible red cell transfusions since blood is not routinely cross matched for the Kell antigen.

The K (K1) antigen is very immunogenic and causes strong reactions in case of mismatched blood transfusion and severe fetal anemia in sensitized mothers. It is produced only after exposure to the antigen as a result of pregnancy or repeated blood transfusions and thus the anti-K antibody is seen frequently in individuals. The k antigen (K2) too is immunogenic but as it is present in most individuals, the anti-k antibody is much less common.

You must be investigated for macrocytic anemia so that it is appropriately treated.

Elevated transaminases after blood transfusion? - Biology

A 36-year-old woman acquired severe human granulocytic anaplasmosis after blood transfusion following a cesarean section. Although intensive treatment with mechanical ventilation was needed, the patient had an excellent recovery. Disease caused by Anaplasma phagocytophilum infection was confirmed in 1 blood donor and in the transfusion recipient.

Human granulocytic anaplasmosis (HGA), an emerging tickborne zoonosis caused by Anaplasma phagocytophilum, has been recognized in the United States since 1994 and in Europe since 1996 (1,2). Most patients acquire A. phagocytophilum infection by tick bite, although individual cases of nosocomial, perinatal, and transfusion-associated transmission have been reported (35). We report a case of severe HGA acquired from blood transfusion.

The Case-Patient

On August 26, 2010, a 36-year-old woman, 29 weeks pregnant without underlying chronic illness, was admitted to the University Medical Center Ljubljana with preeclampsia and restriction of intrauterine growth. Because her previous pregnancy ended in spontaneous abortion, the patient was monitored closely in an inpatient setting. On September 15, an elective cesarean section was performed. Later that day, hemorrhagic shock developed. Surgical revision of the source of the blooding was performed, and she received 6 units of packed erythrocytes and 2 units of fresh frozen plasma, originating from 6 donors. Ten days later, on September 25, the patient became febrile, which was associated with an elevated C-reactive protein level and mild abnormalities in liver enzyme levels, but with no signs of localized infection (Table 1). Antimicrobial drug therapy with amoxicillin/clavulanic acid was initiated, but the regimen was changed after 3 days to gentamicin and metronidazole because the high fever did not abate. At that time, a chest radiograph revealed mild interstitial edema, and a vaginal ultrasound showed no abnormalities.

The patient's condition deteriorated further, and on September 27 she was transferred to an intensive care unit. Tachypnea (30–40 breaths/min) without hypoxia, tachycardia (120 beats/min), elevated temperature (37.8°C), and hypotension (90/60 mm Hg) were recorded at admission. Antimicrobial drug therapy was changed to imipenem, azithromycin, and vancomycin. Computed tomography scan of the chest showed consolidation in the lower right lobe. Blood cultures and other relevant microbiological tests remained negative for infectious agents. Antiphospholipid syndrome was suspected, and treatment with corticosteroids, immunoglobulins, and heparin was initiated. However, corresponding tests did not confirm the diagnosis. Drug therapy was changed to piperacillin/tazobactam, daptomycin, and azithromycin.

The fever continued, laboratory test results worsened (Table 1), and acute respiratory distress syndrome (ARDS) developed. Bone marrow examination, performed because of persistent thrombocytopenia, showed reactive changes. Because of the febrile illness associated with laboratory indicators of inflammation, presence of thrombocytopenia, and elevation of transaminases, as well as the ineffectiveness of treatment, a working diagnosis of HGA was posed, and doxycycline was added to the treatment regimen on October 1.

Figure. . . Histopathology slides from 36-year-old woman with human granulocytic anaplasmosis, Slovenia, 2010. Peripheral blood smear (A, B) bone marrow smear (C). Modified Giemsa staining, original magnification ×1,000. Morulae (clusters of.

The diagnosis was confirmed by demonstration of morulae on examination of whole blood smears by microscopy (Figure), by a positive PCR for DNA coding 16S rRNA of A. phagocytophilum in whole blood, and later by seroconversion to Anaplasma antigens (Table 2). Morulae and A. phagocytophilum DNA were also detected in bone marrow biopsy samples (6,7). In addition, all samples positive by PCR were tested for the groESL operon of A. phagocytophilum, and reliability of products was confirmed by direct sequencing. On the second day of doxycycline treatment, respiratory distress progressed further and artificial ventilation was necessary. However, the next day the patient experienced dramatic improvement on the fourth day after initiation of doxycycline, the breathing tube was removed, and her later clinical course was uneventful. She was discharged at the end of a 14-day treatment course of doxycycline, and at follow-up visits she reported no difficulties.

Because the patient denied having been bitten by ticks, had not left her house for several weeks before admission to the hospital on August 26 because of a complicated pregnancy, was continuously hospitalized for 30 days before the onset of fever on September 25, and received transfusions during her hospital stay, transfusion-associated transmission of HGA was suspected and searched for. Blood taken from the patient for pretransfusion cross-matching on September 15 tested negative by PCR and by immunofluorescence assay for antibodies against A. phagocytophilum. Stored plasma samples from all 6 blood donors, frozen on the day of donation (2 donated blood on August 10, 4 on September 7, 2010), were tested for antibodies against A. phagocytophilum and the presence of corresponding DNA. The results were negative for all but 1 donor. This 42-year-old man, a regular blood donor who lived in a region where sporadic HGA cases had been established (8), reported being an outdoor person who received several tick bites every year (the most recent in July 2010). He donated blood twice in 2010, on May 12 and September 7 blood obtained at the latter visit was transfused as packed erythrocytes to the patient reported here. At the end of August, a self-limited illness had developed in the donor with fever (39°C), myalgia, and arthralgia (Table 2).


HGA is an acute febrile illness that causes headache, myalgia, malaise, elevated levels of C-reactive protein and serum transaminases, leukopenia, and thrombocytopenia the disease seems to have milder manifestations in Europe than in the United States (8,9). The fatality rate is <1% (9), although a literature search did not reveal any report of a fatal case in Europe. The patient fulfilled the criteria for proven HGA (10). She had an acute febrile illness with thrombocytopenia, A. phagocytophilum infection demonstrated by the presence of corresponding DNA in plasma and bone marrow in conjunction with seroconversion, and spectacular improvement after treatment with doxycycline was instituted. The course of her illness was severe and encompassed pneumonia, ARDS, and the need for treatment in the intensive care unit, including mechanical ventilation. Although cough has been reported in 19% of patients with confirmed HGA cases in the United States, pneumonia or ARDS has been documented in only 1% (9). In Europe, pneumonia was recorded for just a few cases, and no data on respiratory failure exist (11).

In our patient, pregnancy, cesarean section, blood loss after the operation, an additional surgical procedure, corticosteroid treatment, and an interval of 6 days before correct diagnosis and treatment could have contributed to the severity of her illness. It is also possible that infection acquired through transfusion results in a more severe illness than infection after the bite of an infected tick. However, only a few reports of presumed transmission of A. phagocytophilum from sources other than ticks have been published (35,12). In a previous single report of transmission by blood transfusion (5), the evidence that HGA was acquired through the transfusion was convincing, but the report could not prove that the patient was free of A. phagocytophilum infection beforehand.

For the patient reported here, findings exclude tick transmission and convincingly favor transfusion-associated transmission of A. phagocytophilum. The latter was confirmed by the presence of A. phagocytophilum DNA in stored plasma specimens of 1 of the 6 blood donors. This donor, who had negative test results for the bacteria 4 months earlier, reported having had an acute self-limited febrile illness 2–3 weeks before blood donation. This infection probably resulted in severe acute HGA in the patient reported here.

A. phagocytophilum remains viable under refrigeration conditions at 4°C for up to 18 days, enabling potential transmission of infection by blood transfusion (13). This case of transfusion-associated HGA in Europe is practical evidence of such transmission and corroborates findings from the United States (5) that transfusion-associated febrile illness with thrombocytopenia could be caused by Anaplasma infection. Because transfusion-associated HGA appears to be very rare, routine screening of blood donors for the presence of A. phagocytophilum genome is not likely to be cost-effective. Nevertheless, when febrile illness associated with leukopenia or thrombocytopenia develops in a patient after transfusion, testing for infection with A. phagocytophilum may be beneficial.

Dr Jereb is a consultant in infectious diseases and intensive care medicine in the Department of Infectious Diseases, University Medical Center Ljubljana. His research interests involve severe infectious diseases and new laboratory markers of bacterial infections.

Etiology of FUO

Causes of FUO are usually divided into 4 categories (see Table: Some Causes of Fever of Unknown Origin (FUO)):

Connective tissue disorders (10 to 20%)

Infections are the most common cause of FUO. In patients with HIV infection, opportunistic infections (eg, tuberculosis infection by atypical mycobacteria, disseminated fungi, or cytomegalovirus) should be sought.

Common connective tissue disorders include systemic lupus erythematosus, rheumatoid arthritis, giant cell arteritis, vasculitis, and juvenile rheumatoid arthritis of adults (adult Still disease).

The most common neoplastic causes are lymphoma, leukemia, renal cell carcinoma, hepatocellular carcinoma, and metastatic carcinomas. However, the incidence of neoplastic causes of FUO has been decreasing, probably because they are being detected by ultrasonography and CT, which are now widely used during initial evaluation.

Important miscellaneous causes include drug reactions, deep venous thrombosis, recurrent pulmonary emboli, sarcoidosis, inflammatory bowel disease, and factitious fever.

No cause of FUO is identified in about 10% of adults.

Some Causes of Fever of Unknown Origin (FUO)

Abdominal or pelvic discomfort, usually tenderness

Sometimes history of surgery, trauma, diverticulosis, peritonitis, or gynecologic procedure

History of being scratched or licked by a cat

Regional adenopathy, Parinaud oculoglandular syndrome, headache

Culture (sometimes of lymph node aspirate), antibody titers, polymerase chain reaction testing

History of blood transfusion from CMV-positive donor

Syndrome that resembles mononucleosis (fatigue, mild hepatitis, splenomegaly, adenopathy), chorioretinitis

Possibly polymerase chain reaction testing

Sore throat, adenopathy, right upper quadrant tenderness, splenomegaly, fatigue

Usually occurring in adolescents and young adults

In older patients, typical findings possibly absent

History of high-risk behaviors (eg, unprotected sex, sharing needles)

Weight loss, night sweats, fatigue, adenopathy, opportunistic infections

4th-generation combination immunoassay

Sometimes testing for HIV RNA (for acute HIV infection)

Often history of risk factors (eg, structural heart disease, prosthetic heart valve, periodontal disease, IV catheter, injection drug use)

Usually a heart murmur, sometimes extracardiac manifestations (eg, splinter hemorrhages, petechiae, Roth spots, Osler nodes, Janeway lesions, joint pain or effusion, splenomegaly)

Serial blood cultures, echocardiography

Visiting or living in an endemic area

Erythema migrans rash, headache, fatigue, Bell palsy, meningitis, radiculopathy, heart block, joint pain and swelling

Localized pain, swelling, erythema

Sometimes MRI (most accurate test), radionuclide scanning with indium-111, bone scanning

Prolonged congestion, headache, facial pain

History of high-risk exposure

Cough, weight loss, fatigue

Use of immunosuppressants

Chest x-ray, tuberculin skin test (PPD), interferon-gamma release assay

Sputum smear for acid-fast bacilli, nucleic acid amplification testing (NAAT), culture of body fluids (eg, gastric aspirates, sputum, cerebrospinal fluid)

History of travel to endemic areas

Exposure to or ingestion of certain animal products

Serologic testing for individual causes

Peripheral blood smear for malaria

Evanescent salmon-pink rash, arthralgias, arthritis, myalgias, cervical adenopathy, sore throat, cough, chest pain

ANA, RF, serum ferritin concentration, x-rays of affected joints

Unilateral headache, visual disturbances

Often symptoms of polymyalgia rheumatica, sometimes jaw claudication

Tenderness of temporal artery when palpated

Erythrocyte sedimentation rate, temporal artery biopsy

Fever, weight loss, myalgias, arthralgias, purpura, hematuria, abdominal pain, testicular pain, angina, livedo reticularis, new-onset hypertension

Biopsy of involved tissues or angiography

History of morning stiffness in shoulders, hips, and neck

Possibly synovitis, bursitis, pitting edema of extremities

Creatinine kinase, ANA, RF, erythrocyte sedimentation rate

Possibly MRI of extremities

Sometimes recent history of infection with Chlamydia, Salmonella, Yersinia, Campylobacter, or Shigella

Asymmetric oligoarthritis, urethritis, conjunctivitis, genital ulcerations

ANA, RF, serologic testing for causative pathogens

Symmetric peripheral polyarthritis, prolonged morning stiffness, subcutaneous rheumatoid nodules in pressure sites (extensor surface of ulna, sacrum, back of head, Achilles tendon)

ANA, RF, anticyclic citrullinated peptide (anti-CCP) antibody, x-rays (to identify bone erosions)

Fatigue, arthralgia, pleuritic chest pain, malar rash, tender swollen joints, mild peripheral edema, Raynaud syndrome, serositis, nephritis, alopecia

Clinical criteria, ANA, antibodies to double-stranded DNA

Abdominal pain, change in bowel habits, hematochezia, weakness, nausea, vomiting, weight loss, fatigue

History of chronic liver disease, abdominal pain, weight loss, early satiety, palpable mass in right upper quadrant

Abdominal ultrasonography and CT, liver biopsy

Sometimes history of myelodysplastic disorder

Fatigue, weight loss, bleeding, pallor, petechiae, ecchymoses, anorexia, splenomegaly, bone pain

Complete blood count, bone marrow examination

Painless adenopathy, weight loss, malaise, night sweats, splenomegaly, hepatomegaly

Symptoms dependent on the site of metastasis (eg, cough and shortness of breath for lung metastasis, headache and dizziness for brain metastasis)

Often asymptomatic, discovered during a routine medical evaluation

Biopsy of suspicious mass or node, imaging tests appropriate for area of concern

Frequently asymptomatic, abnormal indices incidentally detected during screening complete blood count

Testing based on the suspected disorder

Weight loss, night sweats, flank pain, hematuria, palpable flank mass, hypertension

Serum calcium (to check for hypercalcemia), urinalysis, CT of kidneys

Long history of alcohol use

Sometimes ascites, jaundice, small or enlarged liver, gynecomastia, Dupuytren contracture, testicular atrophy

Prothrombin time/partial thromboplastin time, alkaline phosphatase, transaminases, albumin, bilirubin

Sometimes abdominal ultrasonography and CT

Pain, swelling, sometimes redness of leg

Fever coincident with administration of a drug (usually within 7–10 days)

Dramatic, atypical presentation, vague and inconsistent details, knowledge of textbook descriptions, compulsive or habitual lying (pseudologia fantastica)

Abdominal pain, diarrhea (sometimes bloody), weight loss, guaiac-positive stools

Sometimes fistulas, perianal and oral ulcerations, arthralgias

Upper gastrointestinal endoscopy with small-bowel follow-through or CT enterography (Crohn disease)

Colonoscopy (ulcerative colitis or Crohn colitis)

* Patients with FUO may lack typical findings, but such findings should be sought.

ANA = antinuclear antibodies CMV = cytomegalovirus RF = rheumatoid factor.

Infectious hazards

Transfusion-associated hepatitis

The American Society of Hematology (ASH) was just a gleam in William Dameshek's eye when serum hepatitis emerged as a major hazard of blood transfusion among surviving battlefield casualties of World War II. Whereas ASH was rapidly organized in the aftermath of the war, it took nearly 3 decades before the hepatitis B virus, then termed the serum hepatitis virus, was identified and a blood screening test developed. This arduous path from observation to discovery culminated in the serendipitous finding of the Australia antigen in 1963. 1 In the early 1960s, Baruch Blumberg, a geneticist then at the National Institutes of Health (NIH), discovered polymorphisms in human β-lipoproteins using the technique of Ouchterlony immuodiffusion. 2 Harvey Alter, then a clinical fellow in transfusion medicine at NIH, was using the same technique to investigate whether antibodies to human protein variants might cause transfusion reactions. The similarity of approaches, albeit to different ends, led to a collaboration that screened the serum of multiply transfused patients against the serum of diverse global populations for evidence of antibodies to polymorphic proteins. A characteristic of lipoprotein immunoprecipitates was that they stained blue when a lipid stain was applied. In 1963, a precipitin was observed that stained only weakly for lipid, but intensely red when counterstained for protein. It was this “thin red line,” the result of the interaction between the serum of a multiply transfused hemophiliac patient from Brooklyn and the serum of an Australian aborigine, that ultimately became the breakthrough finding in the then semidormant field of hepatitis research (Figure 1). Initially called the “red antigen,” it was subsequently termed the Australia antigen (Au) and, later, the hepatitis B surface antigen (HBsAg).

Au antigen discovery. An Australian aborigine (top) and the precipitin line formed between the aboriginal serum and that of a multiply transfused patient with hemophilia (bottom). The precipitin failed to stain for lipid, but stained red with the azocarmine counterstain for protein. Reprinted with permission of Nature Publishing Group from Alter HJ and Houghton M, Hepatitis C virus and eliminating posttransfusion hepatitis (Nat Med. 20006:1082-1086).

Au antigen discovery. An Australian aborigine (top) and the precipitin line formed between the aboriginal serum and that of a multiply transfused patient with hemophilia (bottom). The precipitin failed to stain for lipid, but stained red with the azocarmine counterstain for protein. Reprinted with permission of Nature Publishing Group from Alter HJ and Houghton M, Hepatitis C virus and eliminating posttransfusion hepatitis (Nat Med. 20006:1082-1086).

Early investigations of Au sought prevalence and disease associations. Interestingly, the antigen was found in 0.1% of the normal donor population but in 10% of patients with leukemia. Thus, when the first paper to describe Au was published in 1965, 1 it made note of the association with leukemia and even speculated that this antigen might be part of the then postulated leukemia virus. At the time of discovery, there was no sense that this cryptic red antigen would unravel a hepatitis mystery that dates to early descriptions by Hippocrates.

In 1964, Blumberg moved to the Institute for Cancer Research in Philadelphia, where he continued to unravel the Au conundrum. He believed at the time that Au was a genetically determined human protein that possibly enhanced susceptibility to leukemia, and thus elected to study patients with Down syndrome, who had an inherited predisposition to leukemia. Although initiated on a faulty premise, study findings were definitive and highly relevant: Down patients who resided in large institutions had an Au prevalence of 30%, whereas those in smaller institutions had a prevalence of 10%, and those living at home only 3% the antigen was absent in newborn Down cases. 3 This observation suggested that Au was not inherited, but rather a manifestation of crowded living conditions and thus possibly related to an unidentified infectious agent. This background was prelude to a serendipitous event. A technologist in the Blumberg lab who had long served as an Au-negative control retested her blood at the time she was feeling ill and turning icteric. Her previously Au-negative blood tested strongly positive, coincident with the onset of classic acute hepatitis. This initial link to a hepatitis virus was confirmed in expanded studies 4 and subsequently shown to be specific for the hepatitis B virus. 5 In retrospect, these findings nicely explained the association with institutionalized patients and the high prevalence in patients with leukemia, who were both highly exposed by transfusion and immunosuppressed with a proclivity to the HBV carrier state.

Thus, through observation, serendipity, and perseverance, a unique antigen was found that proved to be an integral part of the hepatitis B virus envelope protein and then served as the foundation for (1) the first donor screening and diagnostic assay for human hepatitis (2) a highly effective hepatitis B vaccine that not only prevents hepatitis B, but also prevents HBV-associated hepatocellular carcinoma and (3) the recognition of non-A, non-B (NANB) hepatitis by serologic exclusion and hence, ultimately set the stage for the discovery of the hepatitis C virus. This is a heady outcome for a single precipitin line that stained the wrong way.

Watch the video: Hematology. Blood Typing (January 2022).