Abnormal Liver Chemistry Tests Research Articles

S2952 Cefepime-Induced Liver Injury

Introduction: Drug induced liver injury can be a result of many medications and remains as one of the most challenging disorders faced by GI specialists. The most common causes in the Western world include antimicrobials, antiepileptics, anticancer medications, herbal and dietary supplements. It is important to make the distinction between intrinsic and idiosyncratic types of DILI. Intrinsic DILI is capable of causing injury in a predictable pattern in humans when given in high doses. Idiosyncratic DILI only affects susceptible individuals and has less of an association to dosing. The latter being the more difficult type to diagnose and treat. An important value, the R-factor, is used to define hepatotoxicity injury patters. An R-factor < 2 suggests a cholestatic pattern, R-factor > 5 suggests a hepatocellular pattern, and in between a mixed pattern of injury. Early withdrawal of the offending agent is the treatment of choice for any cause of DILI as this prevents progression of acute liver failure. Case Description/Methods: We present a case of a 61 year old male (S, J) with acute elevations in his liver enzymes and alkaline phosphatase. Patient was admitted for alcohol withdrawal. The following day, patient was intubated secondary to hypercapnic respiratory failure and days later developed ventilator associated pneumonia for which he was started on antimicrobial therapy, cefepime and vancomycin. After 9 days of receiving cefepime, patient’s alkaline phosphatase and liver transaminases acutely increased. Patient’s baseline levels were normal on arrival to the hospital. His lab values were the following: ALT 263, AST 507, and alkaline phosphatase 279 with an R factor of 2.8 showing a mixed injury pattern. A right upper quadrant ultrasound showed hepatomegaly and an acute hepatitis panel was ordered which resulted negative. No episodes of significant hypotension were reported. The antibiotic was immediately discontinued with resolution of patient’s levels back to normal. Discussion: Though not as commonly reported, increased ALT, AST or alkaline phosphatase can be a result of cefepime use. Our patient on admission did not have abnormal liver chemistry tests despite his history of alcohol use. R-factor for our patient showed a mixed pattern of liver injury. First line tests when suspecting DILI such as acute viral hepatitis serologies and imaging studies were ordered. Our patient was not re-started on cefepime and his liver enzymes returned to baseline.

Findings of Hepatic Severe Acute Respiratory Syndrome Coronavirus-2 Infection

Background & AimsLiver injury due to coronavirus disease 2019 (COVID-19) is being increasingly recognized. Abnormal liver chemistry tests of varying severities occur in a majority of patients. However, there is a dearth of accompanying liver histologic studies in these patients.MethodsThe current report details the clinical courses of 2 patients having severe COVID-19 hepatitis. Liver biopsies were analyzed under light microscopy, portions of liver tissue were hybridized with a target probe to the severe acute respiratory syndrome coronavirus-2 S gene, and small sections from formalin-fixed paraffin-embedded liver tissue were processed for electron microscopy.ResultsThe liver histology of both cases showed a mixed inflammatory infiltrate with prominent bile duct damage, endotheliitis, and many apoptotic bodies. In situ hybridization and electron microscopy suggest the intrahepatic presence of severe acute respiratory syndrome coronavirus-2, the findings of which may indicate the possibility of direct cell injury.ConclusionsOn the basis of the abundant apoptosis and severe cholangiocyte injury, these histopathologic changes suggest a direct cytopathic injury. Furthermore, some of the histopathologic changes may resemble acute cellular rejection occurring after liver transplantation. These 2 cases demonstrate that severe COVID-19 hepatitis can occur even in the absence of significant involvement of other organs.

Allograft Liver Biopsy

Although not ideal, liver biopsy is the best available method for evaluation of the liver and is considered the gold standard. The most common use of liver biopsies in the posttransplantation setting is for diagnosis of allograft dysfunction presenting with abnormal liver chemistry tests. The causes of allograft dysfunction differ according to time. Early on, preservation and reperfusion injury, infection, donor-related disease, and acute rejection are more common. Later, disease recurrence, de novo disease, and chronic rejection are seen more frequently. A complete history and physical examination are followed by ultrasonography with Doppler. If biliary or vascular causes are suspected, further imaging is performed and stents or surgery planned. If these tests are not diagnostic, a liver biopsy is performed. In addition to diagnosis of allograft dysfunction, protocol liver biopsy can be helpful particularly to diagnose disease recurrence, particularly the immune-mediated diseases, as well as to evaluate the patient for eligibility for immunosuppression minimization and possible withdrawal. Given the risks and cost associated with liver biopsy, several methods are used for evaluation of fibrosis and rejection in the liver allograft. Although very promising, these methods have not been widely validated and are not ready for clinical use. This review contains 9 figures, 2 tables, and 54 references. Key Words: biopsy to diagnose allograft liver dysfunction, disease recurrence after liver transplant, immunosuppression withdrawal after liver transplant, liver biopsy to guide immunosuppression minimization, noninvasive methods to evaluate liver allograft, posttransplant diagnostic liver biopsy, preservation and reperfusion injury, protocol liver biopsy after transplant

Allograft Liver Biopsy

Although not ideal, liver biopsy is the best available method for evaluation of the liver and is considered the gold standard. The most common use of liver biopsies in the posttransplantation setting is for diagnosis of allograft dysfunction presenting with abnormal liver chemistry tests. The causes of allograft dysfunction differ according to time. Early on, preservation and reperfusion injury, infection, donor-related disease, and acute rejection are more common. Later, disease recurrence, de novo disease, and chronic rejection are seen more frequently. A complete history and physical examination are followed by ultrasonography with Doppler. If biliary or vascular causes are suspected, further imaging is performed and stents or surgery planned. If these tests are not diagnostic, a liver biopsy is performed. In addition to diagnosis of allograft dysfunction, protocol liver biopsy can be helpful particularly to diagnose disease recurrence, particularly the immune-mediated diseases, as well as to evaluate the patient for eligibility for immunosuppression minimization and possible withdrawal. Given the risks and cost associated with liver biopsy, several methods are used for evaluation of fibrosis and rejection in the liver allograft. Although very promising, these methods have not been widely validated and are not ready for clinical use. This review contains 9 figures, 2 tables, and 54 references. Key Words: biopsy to diagnose allograft liver dysfunction, disease recurrence after liver transplant, immunosuppression withdrawal after liver transplant, liver biopsy to guide immunosuppression minimization, noninvasive methods to evaluate liver allograft, posttransplant diagnostic liver biopsy, preservation and reperfusion injury, protocol liver biopsy after transplant

Annals for Educators - 21 August 2018.

Annals for Educators - 21 August 2018.

Prevalence of Normal Liver Tests in Patients with Choledocholithiasis Undergoing Endoscopic Retrograde Cholangiopancreatography

Background/Aims: Abnormal liver chemistry tests are a hallmark of common bile duct (CBD) stones. There is little information, however, on the prevalence of and predictors for normal liver chemistry tests in such patients. Methods: Over an 11-year period, all patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) at our Center were prospectively identified. Patients in this study were those with CBD stones found at ERCP and where the indication for ERCP was CBD stones seen on imaging studies or when CBD stones were highly suspected based upon clinical presentation and radiographic and laboratory findings. Liver chemistry tests were recorded from those taken at the time of initial presentation as well as the time closest to ERCP. Results: Of a total of 5,133 patients undergoing ERCP during the study period, the indication was suspicion for CBD stones or for radiographically identified CBD stones in 476 and 593, respectively, with 115 patients having both indications. Of these 1,184 patients, 765 had CBD stones of whom 541 had liver tests. Of these 541, 29 patients (5.4%) were found to consistently have normal liver chemistry tests. Multivariate analysis identified two factors predictive of normal liver tests including age >55 years and the presence of abdominal pain. Conclusions: Although rare, liver tests can be normal in patients with CBD stones. Patients most likely to have normal liver tests included older patients and those with abdominal pain.

Relapse of Intestinal and Hepatic Amebiasis After Treatment

Six months after returning from a trip to Hawaii, a previously healthy 63-year-old man presented with 5 months of right upper-quadrant abdominal pain and non-bloody diarrhea, 3 months of nausea and non-bloody vomiting, and 1 month of fevers, chills, night sweats, and anorexia, culminating in a loss of 20 lbs. Comprehensive laboratory tests were notable for leukocytosis with a white blood cell (WBC) count of 11,300/mm with 88% neutrophils, elevated liver chemistry tests (total bilirubin 0.6 mg/dl, aspartate aminotransferase [AST] 64 U/l, alanine aminotransferase [ALT] 92 U/l, and alkaline phosphatase 674 U/l), and renal failure (blood urea nitrogen 57 mg/dl, creatinine 2.3 mg/dl). Due to his renal insufficiency, non-contrast imaging of the abdomen was obtained, which revealed a 12-cm, thick-walled, multiloculated cystic lesion in the right lobe of the liver (Fig. 1a). Cultures obtained from the patient’s blood, stool, and fluid aspirated from the liver abscess remained sterile. However, serum antibodies to Entamoeba histolytica were positive at a titer of 1:128. The infection was reported to the Department of Health who corroborated the diagnosis with three other cases of Entamoeba histolytica infection that were traced back to a restaurant worker in Hawaii. The patient was treated with oral metronidazole 750 mg three times daily for 10 days, followed by oral paromomycin 1 g three times daily for 10 days. His abdominal pain and diarrhea resolved. A contrast-enhanced abdominal computed tomography (CT) scan, obtained 2 months after finishing his course of antibiotics, documented complete resolution of the liver abscess (Fig. 1b). One year later, the patient again presented with fevers, chills, fatigue, abdominal pain, and diarrhea for 1 month, but this time also reported melena and maroon-colored stools for 1 week. His abdominal pain originated in the epigastrium, radiated to the right upper quadrant, and worsened when lying on his right side. On retrospection, he noted that he had suffered from diarrhea intermittently since his admission the previous year, but each episode had resolved with loperamide. He denied any weight loss and had actually regained 30 lbs. since discharge. He had not traveled anywhere since returning from Hawaii and could not recall any sick contacts. On physical examination, he had a low-grade fever to 100.2 F, but his vitals were otherwise normal. In general, he was well-appearing and without jaundice. He had normal bowel sounds, but his abdomen was distended and mild tenderness could be elicited upon palpation of the epigastrium, right upper-quadrant and right lower-quadrant of the abdomen. He had heme-positive, black-colored stool on rectal examination. Laboratory testing again revealed leukocytosis (WBC 9,500 with 80% neutrophils) and abnormal liver chemistry tests (total bilirubin\0.5 mg/dl, AST 33 U/l, ALT 39 U/l, and alkaline phosphatase 212 U/l). A contrast-enhanced CT of the abdomen showed a 6.0 9 5.2-cm hypo-attenuating mass in segment 4 of the liver with adjacent hyperemia and E. W. Hwang (&) C. A. Cartwright Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University Medical Center, 300 Pasteur Drive, Alway Building, M211, Stanford, CA 94305-5187, USA e-mail: ehwang@stanford.edu

Frequency and predictors of nonalcoholic fatty liver disease in myotonic dystrophy

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that is strongly associated with insulin resistance. Myotonic dystrophy (DM1) is the most common form of adult-onset muscular dystrophy, and there is a high frequency of insulin resistance due to insulin receptor mRNA splicing defects in muscle tissue. The frequency and predictors of NAFLD in this population have not been described. Thirty-six patients with DM1 were prospectively assessed for the presence of NAFLD and insulin resistance. NAFLD was defined by abnormal liver chemistry tests with ultrasound or pathologic evidence of steatosis in the absence of other liver disease. Abnormal liver chemistry tests were found in 44% of DM1 patients (mean ALT 73 +/- 21 U/L, AST 53 +/- 15 U/L), and 87% were attributable to NAFLD. Clinical predictors of NAFLD included increased insulin resistance by the homeostasis model assessment (HOMA) method (9.5 vs. 4.0 U, P = 0.03), elevated fasting insulin (40.4 vs. 16.1 microIU/ml, P = 0.03), abdominal obesity (98.6 vs. 90.8 cm, P = 0.03), elevated triglycerides (195.7 vs. 136.8 mg/dl, P = 0.02), and elevated total cholesterol (213.6 vs. 180.6 mg/dl, P = 0.02). NAFLD is very common and should be considered in the management of DM1. It is strongly associated with markers of insulin resistance and features of the metabolic syndrome. These findings support the role of peripheral insulin resistance in the pathogenesis of NAFLD.

A patient with no known liver disease presenting with a sentinel variceal hemorrhage†

A 45-year-old previously healthy white man presented with a variceal hemorrhage and required endoscopic band ligation. On imaging studies, the patient was found to have a slightly nodular appearing liver and splenomegaly with normal hepatic synthetic function, normal liver chemistry tests, and a platelet count of 125 × 103/μL (normal = 150 × 103 to 450 × 103/μL). Aside from a previous deep vein thrombosis, there was no significant past medical history and no family history of liver disease. An extensive workup for the etiology of his liver disease was unrevealing. A liver biopsy was performed. HPS, hepatoportal sclerosis. There was no cirrhosis. On low-power magnification (Fig. 1A), dilated sinusoids in periportal zones creating “megasinusoids” are apparent (arrowheads). In Fig. 1B, the portal tracts are closely packed together and are densely fibrotic with rounded edges (arrows). There is no open portal vein lumen in any of the three portal tracts shown. A high-power magnification of a portal tract (Fig. 1C) shows near-total obliteration of the portal vein branch by dense fibrosis (phlebosclerosis) (arrow). This constellation of histological findings is consistent with hepatoportal sclerosis (HPS). (hematoxylin & eosin stain; original magnification, Fig. 1A,B ×40, Fig. 1C ×100). HPS is one of the causes of noncirrhotic portal hypertension, synonyms of which include noncirrhotic portal fibrosis, obliterative portal venopathy and idiopathic portal hypertension.1 The cause is obscure and may be related to a prothrombotic disorder or other form of hepatic vascular injury. Portal vein thrombosis is sometimes present. Patients with HPS develop clinical manifestations of portal hypertension (most commonly variceal hemorrhage) and typically have well-preserved hepatic synthetic function with normal or mildly abnormal liver chemistry tests.2 In extreme cases patients develop compromised liver function and require liver transplantation.3 The histological features are heterogeneous; the most common abnormality is absence of portal venules or when present, abnormal fibrotic thickening of vein walls sometimes resulting in total obliteration of the lumen. Periportal dilated structures believed to be herniated portal venules may be seen as well as abnormal dilated sinusoids (megasinusoids).1 The differential diagnosis includes nodular regenerative hyperplasia and incomplete septal cirrhosis.1, 4 Histological features of nodular regenerative hyperplasia may be seen concurrently with HPS4; both are being increasingly described in patients with human immunodeficiency virus infection.5 The diagnosis of HPS can be difficult to make on needle liver biopsy, so provision of a detailed history for the pathologist is requisite and increased awareness of this disorder is essential.

Exacerbation of Sickle Cell Disease Itself as a Cause of Abnormal Liver Chemistry Tests

Liver pathology occurring in patients with sickle cell disease is commonly related to viral hepatitis or hepatic iron deposition due to repeated transfusions; cholestasis and cirrhosis may also occur. Consequently, the differential diagnosis of abnormal liver tests in patients with sickle cell anemia is often complicated. We report the case of a patient presenting with jaundice and abnormal liver biochemistries, without typical evidence of the liver diseases associated with sickle cell anemia. Biochemical markers for viral hepatitis were negative. CT scan only showed hepatomegaly. The liver biopsy revealed marked sinusoidal congestion with red blood cells without significant steatosis or increased iron deposition. The patient's medical history corroborated with biochemical tests and histological examination of the liver suggested that worsening hemolysis related to increased sickling of erythrocytes intrahepatically led to sinusoidal dilatation and probably caused the abnormal liver tests.

Der Patient mit gering erhöhten Leberwerten

The availability of serum blood chemistries for screening both symptomatic and asymptomatic patients has resulted in a marked increase in the number of abnormal liver chemistry tests that must be interpreted by physicians. Usually the first step in the evaluation of a patient with elevated liver enzymes is to repeat the test to confirm the result. If the result is still abnormal, it seems wise to differentiate between a predominant "necrotic pattern" of liver chemistry, as indicated by an elevation of ALT- or AST-activity or a predominant "cholestatic pattern", as indicated by elevated activities of g-GT and alkaline phosphatase. In patients with elevated serum amino transferases hepatic diseases should be excluded primarily with non-invasive serologic tests. The most common causes of elevated amino transferase levels are chronic hepatitis B and C, autoimmunhepatitis, non-alcoholic steatohepatitis, hemochromatosis, Wilson-disease and (only recently recognized) celiac sprue. In the case of a dominant "cholestatic pattern", primary biliary cirrhosis, primary sclerosing cholangitis, but also drugs and granulomatose hepatitis must be excluded. If non-invasive serologic studies remain inconclusive, ultrasound, mini-laparoscopy and liver biopsy will help to establish the final diagnoses.

Histopathological features of L-asparaginase-induced liver disease.

We studied the histopathological changes of liver in four patients who developed hepatomegaly and abnormal liver chemistry tests 2 to 20 days following administration of L-asparaginase as a part of a combination chemotherapy regimen for treatment of acute lymphoblastic leukemia. The severity of the liver disease due to L-asparaginase was unpredictable. One patient developed acute fulminant hepatic failure and required liver transplantation. The most consistent pathological change, observed in all four cases, was diffuse steatosis. Other changes included patchy hepatocyte necrosis, mixed inflammatory cell infiltrates in the portal tracts, and variable degrees of hepatocellular, or canalicular cholestasis, or a combination of these.

Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease

OBJECTIVE: Methotrexate is currently used as a treatment for refractory inflammatory bowel disease. This study sought to evaluate the hepatic effects of long-term methotrexate therapy in patients with inflammatory bowel disease and to determine whether the established guidelines for monitoring methotrexate-related hepatotoxicity with surveillance liver biopsy in patients with psoriasis or rheumatoid arthritis are applicable to these patients. METHODS: Thirty-two patients with inflammatory bowel disease receiving cumulative methotrexate doses of ≥1500 mg were studied. Liver chemistry tests were obtained before and during therapy. Twenty patients underwent liver biopsies as recommended for methotrexate-treated patients with psoriasis; the biopsies were reviewed and graded according to Roenigk’s criteria for methotrexate-induced hepatotoxicity (a grading system for methotrexate hepatotoxicity in psoriasis patients) by a liver pathologist blinded to the methotrexate dose. RESULTS: In patients who had liver biopsies, the mean cumulative methotrexate dose was 2633 mg (range, 1500–5410 mg), given for a mean of 131.7 wk (range, 66–281 wk). Nineteen of 20 patients (95%) had mild histological abnormalities (Roenigk’s grade I and II), and one patient had hepatic fibrosis (Roenigk’s grade IIIB). Abnormal liver chemistry tests, present in 6 of 20 (30%) patients, did not identify the patient with Roenigk’s grade IIIB hepatotoxicity. CONCLUSIONS: Cumulative methotrexate doses up to 5410 mg given up to 281 wk in patients with inflammatory bowel disease are associated with little hepatotoxicity. Surveillance liver biopsies based on cumulative methotrexate doses are not warranted in these patients.

Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease.

Methotrexate is currently used as a treatment for refractory inflammatory bowel disease. This study sought to evaluate the hepatic effects of long-term methotrexate therapy in patients with inflammatory bowel disease and to determine whether the established guidelines for monitoring methotrexate-related hepatotoxicity with surveillance liver biopsy in patients with psoriasis or rheumatoid arthritis are applicable to these patients. Thirty-two patients with inflammatory bowel disease receiving cumulative methotrexate doses of > or = 1500 mg were studied. Liver chemistry tests were obtained before and during therapy. Twenty patients underwent liver biopsies as recommended for methotrexate-treated patients with psoriasis; the biopsies were reviewed and graded according to Roenigk's criteria for methotrexate-induced hepatotoxicity (a grading system for methotrexate hepatotoxicity in psoriasis patients) by a liver pathologist blinded to the methotrexate dose. In patients who had liver biopsies, the mean cumulative methotrexate dose was 2633 mg (range, 1500-5410 mg), given for a mean of 131.7 wk (range, 66-281 wk). Nineteen of 20 patients (95%) had mild histological abnormalities (Roenigk's grade I and II), and one patient had hepatic fibrosis (Roenigk's grade IIIB). Abnormal liver chemistry tests, present in 6 of 20 (30%) patients, did not identify the patient with Roenigk's grade IIIB hepatotoxicity. Cumulative methotrexate doses up to 5410 mg given up to 281 wk in patients with inflammatory bowel disease are associated with little hepatotoxicity. Surveillance liver biopsies based on cumulative methotrexate doses are not warranted in these patients.

LIVER INJURY FROM HERBS AND OTHER BOTANICALS

Many prescription medications have well known hepatotoxic potential. The spectrum of drug-related hepatotoxicity can range from subclinical liver disease with mildly abnormal liver chemistry tests to fulminant hepatic failure (FHF) requiring liver transplantation. Less well recognized is the hepatotoxicity associated with certain over-the-counter preparations, herbal remedies, and naturally occurring plants. The major aspects of herbal medicine-induced liver injury will herein be summarized along with the hepatotoxicity seen with mushroom poisoning, aflatoxin and cocaine ingestion. These herbal and botanical hepatotoxins are shown below. Lastly, the potential hepatoprotective effects of certain herbal preparations will be explored. Herbal Preparations, Medicinal Plants and Other Botanicals with Hepatotoxic Potential Crotalaria Heliotropium Mate' (Paraquay) tea Senecio Symphytum officinale (Comfrey) Ackee fruit Atractylis gummifera Azadirachza indica Berberis vulgaris Callillepsis laureola Cassia angustifolia (Senna) Cocaine (Erythroxylon coca) Cycasin Hedeoma pulegoides and Mentha pulegium (Pennyroyal) Larrea tridentata (Chapparal, creosote bush, greasewood) Sassafras albidum (Sassafras) Scutellaria (Skull cap) Teucrium chamaedrys (Germander) Teucrium polium Valeriana officinalis (Valerian) Viscum album (Mistletoe) Lycopodium serratum (Jin Bu Huan) Ma-huang Syo-saiko-to (Xiao-chai-hu-tang)

Atypical perinuclear antineutrophil cytoplasmic antibodies after colectomy in inflammatory bowel disease.

A typical perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) have been detected in most patients with ulcerative colitis and primary sclerosing cholangitis. Persistent atypical p-ANCA have been observed in ulcerative colitis patients with a prior proctocolectomy, especially with pouchitis, suggesting that this serological marker might be predictive of subsequent development of chronic or refractory pouchitis. This study prospectively evaluated this serological marker in 24 consecutive patients with inflammatory bowel disease and prior colectomies (12 with a clinical diagnosis of ulcerative colitis and 12 with a clinical diagnosis of Crohn's disease involving the colon). Of these, 14 were positive, including 11 with extensive ulcerative colitis and three with Crohn's disease. Although two of three ulcerative colitis patients with pouchitis were positive, eight of eight ulcerative colitis patients having a pelvic pouch with no] pouchitis were also positive, as was a patient who elected to have an end-ileostomy (Brooke's ileostomy). Two patients had abnormal liver chemistry tests. Both had end-stage primary sclerosing cholangitis treated with liver transplantation and were positive for this serological marker. Although atypical p-ANCA may be a marker of persistent inflammation in pelvic pouch patients, a positive test result should not be used for prognosis or as a decision-making parameter for pelvic pouch procedures.

Occult Celiac Disease Associated with Lymphocytic Sclerosing Cholangitis

A 60-year-old male with dermatitis herpetiformis and a previously treated lymphoma involving an inguinal lymph node developed abnormal liver chemistry tests. Because of intermittent diarrhea, additional studies revealed lymphocytic colitis and occult celiac disease that responded to a gluten-free diet. A liver biopsy done to explore persistently abnormal liver chemistry tests showed a portal tract-centred inflammatory process characterized by biliary ductal proliferation, epithelial lymphocytosis and concentric lamellar fibrosis. Quantitation of immunoglobulins was normal and antimitochondrial antibodies were negative. Retrograde cholangiograms showed radiological features typical of primary sclerosing cholangius. The epithelial lymphocycosis reported in gastric, small and large intestinal mucosa of some patients with celiac disease may also be present in the biliary ductal columnar epithelium. This report provides additional evidence that celiac disease may be a far more extensive pathological process.