Fever with jaundice

Fever with jaundice is yellow discolouration of the skin and sclerae (bilirubin over 40 micromol/L, clinically visible from about 35 to 50 micromol/L) with a temperature of 38.0 C or over. Tropical and travel related causes are frequent.

Classification by mechanism

• Prehepatic (haemolytic): unconjugated hyperbilirubinaemia with normal liver enzymes.
• Hepatocellular: ALT and AST raised more than ALP.
• Cholestatic or obstructive: ALP and GGT raised more than transaminases, with conjugated hyperbilirubinaemia.
• Mixed and infiltrative.

R ratio. The ratio of ALT (as a multiple of the upper limit) to ALP (as a multiple of the upper limit) is over 5 in hepatocellular injury, under 2 in cholestatic injury, and 2 to 5 in mixed injury.

Classification by setting. Infection of the liver or biliary tree, systemic infection with secondary liver involvement (sepsis, malaria, typhoid, leptospirosis, rickettsial disease), haemolysis triggered by infection, drug induced liver injury, alcohol related disease, and inflammatory or malignant disease.

Charcot triad. Fever, jaundice and right upper quadrant pain, present in about 25 to 70% of cholangitis. Reynolds pentad adds hypotension and confusion and indicates severe disease.

Acute liver failure. Coagulopathy (INR 1.5 or more) and encephalopathy in a patient without previous liver disease and an illness of under 26 weeks. It is a time critical emergency.

Key distinctions. Dark urine and pale stools indicate conjugated hyperbilirubinaemia. Dark urine without pale stools in a patient with anaemia suggests haemolysis. Painless jaundice with fever in an endemic area suggests malaria, leptospirosis, yellow fever or hepatitis. Biliary pain with fever suggests cholangitis or cholecystitis.

History

• Onset and rate of progression of jaundice, prodrome (anorexia, malaise, aversion to smoking, arthralgia), fever pattern and rigors.
• Right upper quadrant or epigastric pain, biliary colic, previous gallstones, biliary surgery, endoscopic retrograde cholangiopancreatography, weight loss and pruritus.
• Urine and stool colour, vomiting, diarrhoea, bleeding, confusion and sleep reversal.
• Travel, exposure to floodwater, rats and livestock, unsafe food and water (hepatitis A and E), mosquito and tick bites, raw freshwater fish and snails, and contact with jaundiced people.
• Injecting drug use, tattoos, sexual exposure, blood transfusion, healthcare exposure, and mother to child risk (hepatitis B and C).
• Vaccination history: hepatitis A and B, yellow fever and typhoid. Malaria chemoprophylaxis.
• Alcohol quantity and pattern, paracetamol (including repeated supratherapeutic use), antituberculous drugs, amoxicillin with clavulanic acid, flucloxacillin, antiretrovirals (efavirenz, nevirapine), ketoconazole, antiepileptics, herbal and traditional remedies, anabolic steroids and recent new drugs.
• Previous liver disease, sickle cell disease, G6PD deficiency (oxidant drugs, fava beans), HIV, diabetes, and autoimmune disease.
• Pregnancy and gestation.

Examination

• Vital signs, perfusion, Glasgow Coma Scale, glucose, and urine output.
• Depth of jaundice, scratch marks, pallor, bruising, purpura, conjunctival suffusion, and signs of chronic liver disease (spider naevi, palmar erythema, clubbing, ascites, gynaecomastia, parotid enlargement).
• Hepatomegaly (tender, smooth), splenomegaly, right upper quadrant tenderness and Murphy sign, palpable gallbladder (Courvoisier sign), ascites, epigastric mass and surgical scars.
• Asterixis, confusion, foetor hepaticus and hyperreflexia.
• Rash, eschar, lymph nodes, heart murmur, calf tenderness, and meningism.
• Pregnancy: blood pressure, proteinuria and fundal height.

Red flags

• Confusion, asterixis, drowsiness or any encephalopathy with jaundice.
• Hypotension, tachycardia, oliguria or lactate over 2 mmol/L.
• INR over 1.5, glucose under 3 mmol/L, or bleeding.
• Rigors with jaundice and right upper quadrant pain (cholangitis).
• Fever after travel to a malaria area, or hyperparasitaemia, dark urine with anaemia (blackwater fever).
• Calf pain, conjunctival suffusion, haemoptysis or oliguria (leptospirosis).
• Bleeding with jaundice, or contact with viral haemorrhagic fever or yellow fever outbreaks.
• Pregnancy with jaundice, hypertension, abdominal pain or vomiting (acute fatty liver of pregnancy, HELLP syndrome, hepatitis E).
• Paracetamol ingestion over 75 mg/kg, or repeated supratherapeutic dosing.
• Anaemia with jaundice and haemoglobin under 7 g/dL.
• Neutropenia or immunosuppression.

Special groups

• Pregnancy: hepatitis E (fulminant liver failure with mortality of 20 to 30% in the third trimester), acute fatty liver of pregnancy, HELLP syndrome, intrahepatic cholestasis, severe malaria and gallstone disease.
• Older adults: obstructive jaundice from malignancy and cholangitis, and drug reactions.
• Kidney impairment: hepatorenal syndrome, leptospirosis and drug dose adjustment.
• Liver disease: reduce doses of sedatives, avoid NSAIDs and limit paracetamol to 2 g daily.
• Region specific: hepatitis A, E and B, yellow fever, Rift Valley fever, malaria, leptospirosis, amoebic and pyogenic liver abscess, typhoid, liver flukes, hydatid disease, G6PD deficiency, herbal hepatotoxins and aflatoxin exposure.

Biliary and obstructive

• Acute ascending cholangitis (choledocholithiasis, benign stricture, malignancy, biliary parasites).
• Acute cholecystitis with choledocholithiasis or Mirizzi syndrome.
• Gallstone pancreatitis.
• Primary sclerosing cholangitis with bacterial cholangitis.
• Oriental cholangiohepatitis, Ascaris biliary obstruction, and liver fluke infection (Opisthorchis, Clonorchis, Fasciola).
• Ruptured hydatid cyst into the biliary tree.
• Pancreatic head or periampullary carcinoma with cholangitis.
• AIDS cholangiopathy.
• Postprocedure cholangitis.

Hepatocellular infection

• Hepatitis A, E, B, and acute hepatitis C and D.
• Epstein-Barr virus, cytomegalovirus, herpes simplex and varicella zoster hepatitis.
• Yellow fever.
• Viral haemorrhagic fevers: Lassa fever, Ebola, Marburg, Crimean-Congo haemorrhagic fever and Rift Valley fever.
• Dengue with hepatitis.
• Acute HIV infection.
• Leptospirosis (Weil disease).
• Typhoid fever.
• Rickettsial disease and Q fever.
• Brucellosis.
• Secondary syphilis.
• Miliary and hepatic tuberculosis.
• Pyogenic liver abscess and amoebic liver abscess.
• Toxoplasmosis and visceral leishmaniasis.

Haemolytic and haematological

• Severe falciparum malaria, including blackwater fever.
• G6PD deficiency haemolysis triggered by infection or drugs (primaquine, dapsone, nitrofurantoin, sulphonamides, rasburicase).
• Sickle cell disease with intrahepatic cholestasis or hepatic crisis.
• Autoimmune haemolytic anaemia, including cold agglutinin disease after Mycoplasma or Epstein-Barr virus infection.
• Clostridium perfringens sepsis.
• Thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome.
• Babesiosis and Bartonella infection (Oroya fever).
• Haemophagocytic lymphohistiocytosis.
• Lymphoma and leukaemia with hepatic infiltration.

Sepsis related and other

• Sepsis with cholestasis (Gram negative bacteraemia, pneumonia, toxic shock syndrome).
• Drug induced liver injury (paracetamol, antituberculous drugs, amoxicillin with clavulanic acid, flucloxacillin, antiretrovirals, antiepileptics, herbal remedies).
• Alcoholic hepatitis.
• Autoimmune hepatitis.
• Heat stroke and ischaemic hepatitis.
• Budd-Chiari syndrome.
• Acute fatty liver of pregnancy and HELLP syndrome.
• Wilson disease.
• Spontaneous bacterial peritonitis in cirrhosis.

Step 1. Severity. Check Glasgow Coma Scale, glucose, perfusion, INR and lactate. Identify acute liver failure, sepsis and cholangitis at once, because they need treatment before a final diagnosis.

Step 2. First line tests for every patient

• Fractionated bilirubin, ALT, AST, ALP, GGT, albumin, INR, glucose, creatinine, urea, electrolytes and lactate.
• Full blood count with differential and film (parasites, schistocytes, spherocytes, bite cells, Heinz bodies), reticulocyte count, LDH, haptoglobin and direct antiglobulin test when haemolysis is likely (unconjugated bilirubin over 80% of total).
• Malaria rapid test with thick and thin films, repeated every 12 to 24 hours for 3 sets if negative and suspicion remains.
• Blood cultures, two sets before antibiotics.
• Urinalysis (bilirubin, urobilinogen, protein, blood) and pregnancy test.
• Paracetamol level in all patients with unexplained hepatocellular injury.
• Chest radiograph and abdominal ultrasound within 24 hours (duct dilatation over 6 mm, gallstones, abscess, ascites, hepatic veins, hepatomegaly).

Step 3. Targeted tests

• Hepatitis: hepatitis A IgM, HBsAg with anti HBc IgM, hepatitis C antibody with RNA, hepatitis E IgM with RNA, and hepatitis D when HBsAg positive.
• HIV test, syphilis serology, Epstein-Barr virus and cytomegalovirus serology and PCR, herpes simplex PCR (in pregnancy and immunosuppression).
• Leptospirosis PCR in blood (first 10 days) and urine (later), with microscopic agglutination test or IgM.
• Typhoid blood culture. Brucella blood culture with prolonged incubation and serology. Rickettsial PCR and serology. Yellow fever and dengue RT PCR and IgM. Viral haemorrhagic fever tests only after contacting public health.
• G6PD enzyme assay (may be falsely normal during acute haemolysis and reticulocytosis, so repeat 2 to 3 months later).
• Autoimmune markers (ANA, anti smooth muscle antibody, IgG), ferritin, ceruloplasmin and copper in young patients.
• MRCP or CT for suspected obstruction, abscess, or tumour. Endoscopic retrograde cholangiopancreatography is therapeutic. Endoscopic ultrasound for small stones.
• Liver biopsy (transjugular when coagulopathic) when the cause remains unclear after investigation.
• Ascitic fluid analysis when ascites is present (neutrophils 250/microlitre or more indicates spontaneous bacterial peritonitis).

Step 4. Severity of cholangitis. Organ dysfunction (any of hypotension needing vasopressor, altered consciousness, PaO2 to FiO2 ratio under 300, creatinine over 176 micromol/L, INR over 1.5, platelets under 100 x 10^9/L) defines severe disease. Moderate disease has any 2 of white count over 12 or under 4 x 10^9/L, temperature of 39 C or over, age 75 years or over, bilirubin 85 micromol/L or over, or hypoalbuminaemia. Otherwise it is mild.

Step 5. Prognostic markers. In paracetamol induced liver failure poor prognosis is indicated by arterial pH under 7.30 after resuscitation, or INR over 6.5 with creatinine over 300 micromol/L and grade 3 to 4 encephalopathy. Alcoholic hepatitis severity uses the discriminant function (4.6 x prolongation of prothrombin time in seconds + bilirubin in mg/dL), where 32 or more indicates severe disease.

Limits. Charcot triad lacks sensitivity. Ultrasound can miss common bile duct stones in up to 50% of patients. Malaria rapid tests can be negative in low parasitaemia. Transaminases may fall in fulminant failure as the liver shrinks, so a falling ALT with rising INR is ominous. Liver enzymes may be normal early in infection.

Immediate

• Oxygen, intravenous access, blood cultures, glucose, and lactate. Treat hypoglycaemia with dextrose 25 g intravenously, then 10% dextrose infusion.
• Sepsis or shock: crystalloid boluses of 250 to 500 mL with reassessment (up to 30 mL/kg in 3 hours when clearly hypovolaemic), noradrenaline to keep mean arterial pressure at 65 mmHg or over, and antibiotics within 1 hour.
• Empirical antibiotics when sepsis, cholangitis or typhoid is possible: piperacillin with tazobactam 4.5 g intravenously every 6 hours (3.375 g every 6 hours at creatinine clearance 20 to 40 mL/min, 2.25 g every 6 hours under 20 mL/min), or ceftriaxone 2 g intravenously once daily with metronidazole 500 mg intravenously every 8 hours. For hospital acquired or severe disease use meropenem 1 g intravenously every 8 hours (1 g every 12 hours at creatinine clearance 26 to 50 mL/min, 500 mg every 12 hours at 10 to 25 mL/min, 500 mg every 24 hours under 10 mL/min).
• Add doxycycline 100 mg orally or intravenously twice daily when leptospirosis or rickettsial disease is possible.
• Isolate patients with suspected viral haemorrhagic fever, yellow fever or hepatitis A or E with faecal incontinence, and apply contact and enteric precautions.
• Vitamin K: phytomenadione 10 mg intravenously once daily for 3 days when INR is raised in cholestasis. Do not give fresh frozen plasma to correct INR in acute liver failure unless bleeding or before an invasive procedure.

Cholangitis

• Continue the antibiotic regimen for 4 to 7 days after biliary drainage (longer with bacteraemia from Enterococcus or Staphylococcus aureus). Add vancomycin 15 to 20 mg/kg intravenously every 8 to 12 hours when MRSA or enterococcus is likely.
• Biliary drainage by endoscopic retrograde cholangiopancreatography with sphincterotomy and stone extraction or stent: urgent (as soon as resuscitated) for severe disease, within 24 to 48 hours for moderate disease, and when mild disease does not improve in 24 hours. Percutaneous transhepatic drainage or surgery when endoscopic drainage fails.
• Cholecystectomy after recovery for gallstone disease.

Malaria

• Severe malaria (jaundice with bilirubin over 50 micromol/L plus parasitaemia): artesunate 2.4 mg/kg intravenously at 0, 12 and 24 hours then once daily, followed by a full course of oral artemether with lumefantrine after at least 24 hours of parenteral therapy. Monitor glucose every 4 to 6 hours, transfuse for haemoglobin under 7 g/dL, and check haemoglobin at 1, 2 and 4 weeks for delayed haemolysis.
• Uncomplicated falciparum malaria: artemether with lumefantrine (20 mg/120 mg tablets), 4 tablets at 0, 8, 24, 36, 48 and 60 hours with fatty food for 35 kg or over.
• Primaquine only after G6PD testing.

Leptospirosis

• Mild: doxycycline 100 mg orally twice daily for 7 days.
• Severe or Weil disease: benzylpenicillin 1.5 million units intravenously every 6 hours, or ceftriaxone 1 g intravenously once daily, for 7 days. Expect a Jarisch-Herxheimer reaction. Early dialysis for oliguric renal failure, and ventilatory support for pulmonary haemorrhage.

Viral hepatitis

• Hepatitis A and E: supportive care with fluids, rest, nutrition and avoidance of alcohol and hepatotoxic drugs. Hepatitis E in pregnancy needs admission, close monitoring of INR and mental state, and obstetric review.
• Acute hepatitis B with INR over 1.5 or prolonged severe course: entecavir 0.5 mg orally once daily on an empty stomach (adjusted to creatinine clearance), or tenofovir disoproxil 300 mg orally once daily (every 48 hours at creatinine clearance 30 to 49 mL/min). Refer to hepatology.
• Herpes simplex or varicella zoster hepatitis: aciclovir 10 mg/kg intravenously every 8 hours (adjusted for kidney function).
• Acute hepatitis C: refer for antiviral therapy at the specialist liver service.

Liver abscess and other infection

• Amoebic liver abscess: metronidazole 500 to 800 mg orally (or 500 mg intravenously) three times daily for 7 to 10 days, then diloxanide furoate 500 mg orally three times daily for 10 days. Aspirate abscesses over 5 cm, in the left lobe, or not responding after 72 hours.
• Pyogenic liver abscess: ceftriaxone 2 g intravenously once daily with metronidazole 500 mg intravenously every 8 hours, for at least 2 weeks intravenously then oral therapy to complete 4 to 6 weeks total. Percutaneous drainage for lesions over 5 cm.
• Typhoid fever: azithromycin 500 mg orally once daily for 7 days, or ceftriaxone 2 g intravenously once daily for 7 to 14 days.
• Spontaneous bacterial peritonitis: ceftriaxone 2 g intravenously once daily for 5 days with albumin 1.5 g/kg on day 1 and 1 g/kg on day 3.
• Brucellosis: doxycycline 100 mg orally twice daily for 6 weeks plus gentamicin 5 mg/kg intravenously once daily for 7 days.
• Yellow fever and other viral haemorrhagic fevers: supportive care in an isolation unit.

Drug and toxin related

• Stop all suspected hepatotoxic drugs (continue antituberculous therapy only under specialist direction using modified regimens).
• Paracetamol overdose: acetylcysteine 150 mg/kg intravenously over 1 hour, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours (300 mg/kg over 21 hours), started as early as possible. Continue when INR is raised or ALT is rising, and consider acetylcysteine in non paracetamol acute liver failure under specialist direction.
• Alcoholic hepatitis: nutritional support, thiamine 100 mg intravenously or orally daily, and prednisolone 40 mg orally daily for 28 days in severe disease without active infection, gastrointestinal bleeding or renal failure, stopping at day 7 if the Lille score is over 0.45.

Haemolysis

• G6PD deficiency: stop the trigger, maintain hydration, transfuse for haemoglobin under 7 g/dL or symptoms, and give folic acid 5 mg orally daily. Treat the infection.
• Autoimmune haemolysis: prednisolone 1 mg/kg orally daily (maximum 80 mg) under haematology direction.
• Thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: urgent haematology referral.

Pregnancy

• Acute fatty liver of pregnancy and HELLP syndrome: stabilise (blood pressure control, magnesium sulphate for eclampsia prophylaxis, correct coagulopathy and glucose) and deliver after maternal stabilisation.
• Severe malaria: artesunate in all trimesters.

Acute liver failure

• Admit to a high dependency or intensive care unit and contact a liver transplant centre early (INR over 1.5 with any encephalopathy).
• Monitor glucose hourly, avoid sedatives, treat sepsis early, correct electrolytes, and give lactulose only for grade 1 to 2 encephalopathy. Control raised intracranial pressure with head elevation and 3% saline 150 to 250 mL or mannitol under specialist direction. Avoid nephrotoxic drugs and use renal replacement therapy as needed.

Symptomatic care. Paracetamol 500 mg to 1 g orally every 6 hours with a maximum of 2 g daily in liver disease. Avoid NSAIDs. Antiemetic: ondansetron 4 mg orally or intravenously every 8 hours. Colestyramine 4 g orally once daily (up to 4 g three times daily) for pruritus in cholestasis, taken 1 hour before or 4 to 6 hours after other drugs.

Monitoring. Vital signs and glucose every 1 to 4 hours when unwell. Daily bilirubin, ALT, INR, creatinine, electrolytes and blood count, with INR every 6 to 12 hours in acute liver failure. Repeat malaria films at 24 and 48 hours.

Referral and escalation. Surgery or gastroenterology for biliary obstruction and drainage. Hepatology and transplant centre for acute liver failure. Infectious diseases for travel related disease and unexplained fever. Haematology for haemolysis and thrombotic microangiopathy. Obstetrics for pregnancy related causes. Public health for hepatitis A and E, yellow fever, leptospirosis, typhoid and viral haemorrhagic fever.

Admission criteria. Any red flag, encephalopathy, INR over 1.5, bilirubin over 100 micromol/L with fever, cholangitis, severe or travel related malaria, suspected viral haemorrhagic fever, pregnancy, inability to take oral fluids, and diagnostic uncertainty.

Discharge and follow up. Discharge only when afebrile, eating, with improving bilirubin and INR, and with review within 48 to 72 hours. Repeat liver tests at 1 to 2 weeks. Hepatitis B contacts need vaccination and immunoglobulin. Safety net advice: return for confusion, drowsiness, black or bloody stools, vomiting blood, rigors, severe abdominal pain, dark urine with reduced volume, or bleeding.