An Internal Medicine Approach to Abnormal Liver Chemistry Studies

Causes of liver damage include:

Toxic

• Acute alcoholic hepatitis (fever, leukocytosis, abnormal liver chemistry studies)
• acetaminophen
• Amanita poisoning (history of mushroom ingestion)
• Other drugs

Infectious

• Viruses
  • HAV (food-related outbreak with a relatively short incubation period)
  • HBV
  • HCV
  • HEV (Pregnant patient from Southeast Asia with oro-fecally transmitted fulminant hepatitis with a very long (8 week) incubation period)
  • CMV (teenager or young adult with a mono-like picture but heterophile antibody negative)
  • EBV (teenager or young adult with pharyngitis and splenomegaly)
  • HSV (immunocompromised patient with fever, abdominal pain, leukopenia, hypertransaminasemia)
  • VZV
• Bacteria:
  • sepsis
  • acute acalculous cholecystitis
  • Biliary sepsis
  • Gonococcal or chlamydial perihepatitis (a.k.a. Fitz-Hugh-Curtis syndrome; young sexually active woman worth fever, pleuritic right upper quadrant pain; look for vaginal discharge and adnexal tenderness on pelvic examination)
  • salmonellosis (diarrhea, “rose spots” on abdomen, stepwise fever, temperature-pulse disparity)
  • Listeriosis
  • syphilitic hepatitis (rash on palms and soles)
  • leptospirosis (animal exposure, conjunctival suffusion)
  • Rocky Mountain Spotted Fever (Tick exposure and petechial rash on wrists and ankles, then palms and soles, then generalized)
• Protozoa: entamebiasis (recent travel to South America presenting with
• Helminths:
  • echinococcosis (cyclical biliary pain with eosinophilia in patient with exposure to farm animals, with liver cysts with internal serpentine linear structures),
  • schistosomiasis

Cholestatic (impaired bile flow)

• Extrahepatic
  • Choledocholithiasis (stone in the common bile duct)
  • Cholangiocarcinoma (weight loss, jaundice, silver colored stools)
  • Pancreatic cancer (rapid onset of itchiness, painless jaundice, dark urine, pale stools)
  • Sclerosing cholangitis (jaundice, liver dysfunction, itching,  in a patient with inflammatory bowel disease; “string of beads” on imaging)
• Intrahepatic
  • Hormones and medications (pregnancy, estrogens)
  • Primary biliary cirrhosis (middle-aged female with an otherwise unremarkable medical history who presents with itchiness)

Ischemic/congestive

• shock liver (history of hypotension)
• Passive hepatic congestion (from heart failure, etc.)
• Budd-Chiari syndrome (obstruction of hepatic vein, leading to ascites, RUQ pain, usually in the setting of a hypercoagulable state)
• Sinusoidal obstruction syndrome (obstruction of hepatic venules, venoocclusive disease)
• Portal vein thrombosis (abdominal pain, portal hypertension)

Metabolic

• Nonalcoholic steatohepatitis (NASH, often in a patient with obesity, diabetes mellitus, insulin resistance)
• Pregnancy
  • hyperemesis gravidarum
  • intrahepatic cholestasis of pregnancy
  • acute fatty liver of pregnancy
  • HELLP syndrome (Hemolysis, Elevated Liver chemistries Low Platelets)
  • Note that viruses, drugs and gallstones are the more common causes in early pregnancy
  • elevated alkaline phosphatase is seen in normal pregnancy
• hyperthyroidism
• hemochromatosis (fatigue, loss of libido, arthropathy, “bronzed” skin, joint pains, diabetes for no good reason!, cardiomyopathy)
• celiac disease (elevated aminotransferases and unexplained diarrhea, iron deficiency anemia, osteoporosis or pruritus that does not respond to glucocorticoids)
• Wilson’s disease (hemolytic anemia, movement disorders, neuropsychiatric symptoms, Kayser-Fleischer rings)
• α₁-antitrypsin deficiency (young person or nonsmoker with COPD and abnormal liver studies)

Autoimmune

The main “players” from a workup standpoint are:

• markers of necroinflammatory activity of the liver parenchyma itself: AST and ALT, the aminotransferases
• Marker of cholestasis or poor excretory function: alkaline phosphatase and bilirubin, especially direct bilirubin
• Markers of chronicity (or cirrhosis) : PT/INR, albumen, platelets, sodium, and to an extent, even serum bicarbonate, potassium, BUN and creatinine.

The above labs should be ordered in every case of suspected liver problems.

The picture, however, from a biochemical standpoint is seldom “clean.” The reason is that cholestasis can cause a necroinflammatory response, and a necroinflammatory response can cause cholestasis, making it difficult to ascertain the pattern of injury from chemistry studies alone. Imaging and instrumentation are often required.

In concept, there are several distinct laboratory and clinical patterns that one should be familiar with:

• Acute liver failure: acute derangement of liver chemistry studies, encephalopathy, and increased INR.
• Hepatocellular injury pattern: as the term implies, this denotes direct damage to hepatocytes which “spill” aminotransferases into the blood, with often normal, or near normal, alkaline phosphatase and bilirubin. The main causes of this pattern of injury are viruses, toxins and ischemia. Other causes of hepatocellular pattern injury include metabolic diseases
• Cholestatic injury pattern: denotes impaired excretion of bile, sometimes with consequential indirect damage to hepatocytes. Thus, the most characteristic laboratory pattern is elevated alkaline phosphatase and conjugated bilirubin, with only mild elevation in ALT and AST. The main causes of this pattern of injury are biliary obstruction. Sometimes hepatocellular dysfunction (hepatitis, medications, sepsis, primary biliary cirrhosis) can also result in a cholestatic picture. In any event, patients with a cholestatic pattern of injury require imaging of the common bile duct, generally, with an ultrasound of the right upper quadrant of the abdomen, to rule out obstruction. Conjugated hyperbilirubinemia is evidence of cholestasis and requires a workup for obstructive causes as well.
• Isolated unconjugated hyperbilirubinemia: increased bilirubin, with normal AST, ALT and alkaline phosphatase. The main causes of this pattern of injury are hemolysis, ineffective erythropoiesis, hematoma reabsorption. Thus, the workup here is should be for hemolysis (CBC, blood smear, reticulocyte count, LDH, and haptoglobin)
• Conjugated hyperbilirubinemia: this points to cholestasis (impaired bile flow) or to hepatocellular disease, and is often seen in patient with dark urine and pale stools.
• Isolated elevated alkaline phosphatase: this can be seen either in hepatobiliary disease or in other conditions, such as normal pregnancy, growing children, hyperthyroidism, Paget’s disease of the bone, renal cell carcinoma, and temporal arteritis.
• Infiltrative: malignant (colon > stomach > pancreas > breast), granulomatous (tuberculosis, sarcoidosis, histoplasmosis), infectious (amoebic, bacterial)
• Mixed or indeterminate: for example, viral hepatitis can cause biliary epithelial damage and thereby cholestasis

In reality, there is often no distinct pattern of injury.

Jaundice:

The clinical finding of jaundice always indicates a pathologic state. Its causes are numerous, but the common denominator is hyperbilirubinemia, the accumulation of bile pigments in the blood. Such accumulation may be prehepatic, hepatic, or posthepatic in origin, resulting from excess pigment production, defective processing by the liver, or obstruction of the excretion of bile in the biliary tract, respectively. When the serum level of bilirubin reaches 2.5 mg %, yellow staining of tissues is evident, and this is most easily detectable in areas of the body where structures have large components of elastic tissue, e.g., the conjunctivae, the palate, and the sublingual mucosa.

Differential Diagnosis of Infectious Disease (1996)

Icterus is synonymous with jaundice. Stedman’s (2012).

The first step in evaluating Jaundice or abnormal liver chemistry studies is to rule out toxic causes.

Laboratory and imaging studies:

• platelets, INR, albumen, cholesterol, sodium (if chronic liver disease is suspected)
• BUN, creatinine, potassium, bicarbonate (if hepatorenal syndrome is suspected)
• serum glucose (if NASH is suspected)
• Hepatitis A, B & C panels, acetaminophen, salicylate and ETOH levels (if hepatocellular pattern of injury is suspected)
• pregnancy testing and urinalysis (if pregnancy is suspected)
• lipase (if gallstone pancreatitis is suspected)
• serial troponins and liver chemistry studies, LDH, electrocardiogram, chest radiograph, echocardiogram (if shock liver is suspected)
• serum ammonia level (if hepatic encephalopathy is suspected)
• paracentesis (if SBP is suspected)
• serum iron, transferrin, ferritin, serum glucose, HBA1C; HFE genetic testing, and possibly MRI of the abdomen, echocardiogram, and radiographs of involved joints (if hemochromatosis is suspected)
• antimitochondrial antibodies (if primary biliary cirrhosis is suspected)
• anti-smooth muscle antibody, ANA, anti-soluble liver antigen, anti-LKM1 (if autoimmune hepatitis is suspected)
• serum free copper, ceruloplasmin levels, and 24-hour urinary copper excretion, hemolysis workup (hematocrit, peripheral blood smear, reticulocyte count, LDH, haptoglobin), brain MRI if neuropsychiatric symptoms are present (if Wilson’s disease is suspected)
• antimitochondrial antibodies (if primary biliary cirrhosis is suspected)
• serum α₁-antitrypsin level, chest radiograph (if α₁-antitrypsin deficiency is suspected)
• α-Fetoprotein (if hepatocellular carcinoma is suspected)
• CT or ultrasound of liver, stool for ova and parasites, enzymatic immunoassay of stool, serology (if amebic liver disease is suspected)
• 5′-NT or GGT (if source of alkaline phosphatase is uncertain)
• If hepatobiliary disease is suspected on the basis of right upper quadrant pain and/or cholestatic injury laboratory pattern, get right upper quadrant ultrasound without Doppler. If common bile duct obstruction  is found, then:
  • ERCP if it is believed that obstruction can be relieved
  • MRCP if sclerosing cholangitis is suspected

• right upper quadrant ultrasound with Doppler (if hepatic venous outflow obstruction is suspected or if portal vein thrombosis is suspected)
• triple-phase CT (noncontrast, arterial phase, venous phase) of liver (if a space occupying lesion is suspected)
• delayed phase CT of liver (ff cholangiocarcinoma is suspected)
• plain abdominal radiograph or CT abdomen (if cholecystenteric fistula (gallstone ileus) is suspected)
• chest radiograph (if ARDS, hepatopulmonary syndrome, hepatic hydrothorax are suspected)
• Other tests: TSH, urinalysis (for bilirubin!)

And finally, a biopsy should be considered if a diagnosis cannot be made with any of the above means.

“Textbook” associations (i.e. free points on the Boards!):

• aminotransferases in the thousands: differential is fairly narrow with viruses, toxins, and ischemia being the main causes.
• aminotransferases in the thousands with elevated LDH: shock liver
• Critically ill or septic patient: sepsis, biliary sepsis, or acute acalculous cholecystitis
• Biliary cholic with air in biliary tree and small bowel obstruction: cholecystenteric fistula (gallstone ileus)
• Arthralgias: viral hepatitides, hemochromatosis
• Concomitant autoimmune diseases: autoimmune hepatitis (treat with prednisone), or primary biliary cirrhosis
• Imaging shows (1) Stone impacted in cystic duct, (2) dilated common bile duct above level of cystic duct, (3) smooth curved segmental stenosis of common hepatic duct : Mirizzi Syndrome
• RUQ pain, diarrhea, and obstructive jaundice in AIDS patient: AIDS cholangiopathy (Cryptosporidium parvum)
• Sickle Cell Disease: acute hepatic crisis, hemolysis and/or pigmented bile stones
• Tick exposure, elevated liver studies but no rash: Ehrlichiosis
• Travel to places with poor sanitation: Amebiasis (Entamoeba histolytica)
• Livestock exposure, headache, pneumonitis, no rash: Coxiella burnetii (Q fever)
• Tick exposure, hemolysis: babesiosis (a hemolytic, not a hepatic process)
• History of travel, with anemia and recurrent fevers: malaria
• Rabbits: tularemia
• Pregnant or elderly patient growing out gram-positive rods: Listeriosis
• Hypercoagulable state: hepatic venous outflow obstruction
• Africa: Schistosomiasis (patient from endemic area presenting with portal hypertension, eosinophilia, sans stigmata of chronic liver disease)

References

• American College of Physicians (2012), Board Basics 3 (reviewed here)
• Acing the Hepatology Questions on the GI Board Exam: The Ultimate Crunch-Time Resource (2011, reviewed here) by Brennan M. R. Spiegel MD
• Differential Diagnosis of Infectious Disease (1996, reviewed here) by David Schlossberg MD
• Instant Workups: A clinical Guide to Obstetrics and Gynecologic Care (2009)
• The Merck Manual for Health Care Professionals (2012)
• Pocket Medicine (2010)
• Radiology Review Manual (2011)
• Stedman’s Medical Dictionary for the Health Professions and Nursing (2011) (reviewed here)
• The Washington Manual of Medical Therapeutics (2010)