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https://www.msdmanuals.com/professional/hepatic-and-biliary-disorders/approach-to-the-patient-with-liver-disease/jaundice

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History of present illness should include onset and duration of jaundice. Hyperbilirubinemia can cause urine to darken before jaundice is visible. Therefore, the onset of dark urine indicates onset of hyperbilirubinemia more accurately than onset of jaundice. Important associated symptoms include fever, prodromal symptoms (eg, fever, malaise, myalgias) before jaundice, changes in stool color, pruritus, steatorrhea, and abdominal pain (including location, severity, duration, and radiation). Important symptoms suggesting severe disease include nausea and vomiting, weight loss, and possible symptoms of coagulopathy (eg, easy bruising or bleeding, tarry or bloody stools).

Past medical history should identify known causative disorders, such as hepatobiliary disease (eg, gallstones, hepatitis, cirrhosis); disorders that can cause hemolysis (eg, hemoglobinopathy, glucose-6-phosphate dehydrogenase [G6PD] deficiency); and disorders associated with liver or biliary disease, including inflammatory bowel disease, infiltrative disorders (eg, amyloidosis, lymphoma, sarcoidosis, tuberculosis), and HIV infection or AIDS.

Surgical history should include questions about previous surgery on the biliary tract (a potential cause of strictures).

Family history should include questions about recurrent, mild jaundice in family members and diagnosed hereditary liver disorders. The patient's history of recreational drug and alcohol use should be corroborated by friends or family members when possible.

Vital signs are reviewed for fever and signs of systemic toxicity (eg, hypotension, tachycardia).

General appearance is noted, particularly for cachexia and lethargy.

The abdomen is inspected for collateral vasculature, ascites, and surgical scars. The liver is palpated for hepatomegaly, masses, nodularity, and tenderness. The spleen is palpated for splenomegaly. The abdomen is examined for umbilical hernia, shifting dullness, fluid wave, masses, and tenderness. The rectum is examined for gross or occult blood.

Men are checked for testicular atrophy and gynecomastia.

Neurologic examination includes mental status assessment and evaluation for asterixis (a characteristic flapping tremor of the hands).

The skin is examined for jaundice, palmar erythema, needle tracks, vascular spiders, excoriations, xanthomas (consistent with primary biliary cholangitis), paucity of axillary and pubic hair, hyperpigmentation, ecchymoses, petechiae, and purpura.

The following findings are of particular concern:

Severity of illness is indicated mainly by the degree (if any) of hepatic dysfunction. Ascending cholangitis is a concern because it requires emergency treatment.

Severe hepatic dysfunction is indicated by encephalopathy (eg, mental status change, asterixis) or coagulopathy (eg, easy bleeding, purpura, tarry or heme-positive stool), particularly in patients with signs of portal hypertension (eg, abdominal collateral vasculature, ascites, splenomegaly). Massive upper GI bleeding suggests variceal bleeding due to portal hypertension (and possibly coagulopathy).

Ascending cholangitis is suggested by fever and marked, continuous right upper quadrant abdominal pain; acute pancreatitis with biliary obstruction (eg, due to a common duct stone or pancreatic pseudocyst) may manifest similarly.

Cause of jaundice may be suggested by the following:

Blood tests include measurement of total and direct bilirubin, aminotransferase, and alkaline phosphatase levels in all patients. Results help differentiate cholestasis from hepatocellular dysfunction (important because patients with cholestasis usually require imaging tests):

Hepatocellular dysfunction: Marked aminotransferase elevation (> 500 U/L [8.35 microkat/L]) and moderate alkaline phosphatase elevation (< 3 times normal)

Cholestasis: Moderate aminotransferase elevation (< 200 U/L [3.34 microkat/L]) and marked alkaline phosphatase elevation (> 3 times normal)

Also, patients with hepatocellular dysfunction or cholestasis have dark urine due to bilirubinuria because conjugated bilirubin is excreted in urine; unconjugated bilirubin is not. Bilirubin fractionation also differentiates conjugated from unconjugated forms. When aminotransferase and alkaline phosphatase levels are normal, fractionation of bilirubin can help suggest causes, such as Gilbert syndrome or hemolysis (unconjugated) vs Dubin-Johnson syndrome or Rotor syndrome (conjugated).

Other blood tests are done based on clinical suspicion and initial test findings, as for the following:

Imaging is done if pain suggests extrahepatic obstruction or cholangitis or if blood test results suggest cholestasis.

Abdominal ultrasonography is usually done first; usually, it is highly accurate in detecting extrahepatic obstruction. CT and MRI are alternatives. Ultrasonography is usually more accurate for gallstones, and CT is more accurate for pancreatic lesions. All these tests can detect abnormalities in the biliary tree and focal liver lesions but are less accurate in detecting diffuse hepatocellular disorders (eg, hepatitis, cirrhosis).

Liver biopsy is not commonly required but can help diagnose certain disorders (eg, disorders causing intrahepatic cholestasis, some kinds of hepatitis, some infiltrative disorders, Dubin-Johnson syndrome, hemochromatosis, Wilson disease). Biopsy can also help when liver enzyme abnormalities are unexplained by other tests.

Laparoscopy (peritoneoscopy) allows direct inspection of the liver and gallbladder without the trauma of a full laparotomy. Unexplained cholestatic jaundice warrants laparoscopy occasionally and diagnostic laparotomy rarely.

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Jaundice - Hepatic and Biliary Disorders - MSD Manual Professional Edition

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History of present illness should include onset and duration of jaundice. Hyperbilirubinemia can cause urine to darken before jaundice is visible. Therefore, the onset of dark urine indicates onset of hyperbilirubinemia more accurately than onset of jaundice.

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Bilirubin metabolism

1. Bilirubin is produced from breakdown of mature red cells by Kupffer cells in the liver and reticuloendothelial system; 15% of bilirubin is formed from catabolism of other haemcontaining proteins

Normally, 250–300 mg daily.

2. unconjugated bilirubin is water-insoluble, due to internal hydrogen bonding, and is transported to the liver attached to albumin.

3. Bilirubin dissociates from albumin and is taken up by hepatic cell membranes and transported to the endoplasmic reticulum by cytoplasmic proteins, where it is conjugated with glucuronic acid and excreted into bile.

4.. conjugated bilirubin is water-soluble and is actively secreted into biliary canaliculi and excreted into the intestine within bile

5. not absorbed from the small intestine because of its large molecular size

6. In the terminal ileum, bacterial enzymes hydrolyse the molecule, releasing free bilirubin which is then reduced to urobilinogen, some of which is excreted in the stools as stercobilinogen. The remainder is absorbed by the terminal ileum, passes to the liver via the enterohepatic circulation, and is re-excreted into bile. Then excreted kidneys

= When hepatic excretion of conjugated bilirubin is impaired, a small amount is strongly bound to serum albumin and is not excreted by the kidneys; it accounts for the persistent hyperbilirubinemia

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types of jaundice

Jaundice (icterus) is detectable clinically when the serum bilirubin is >50 μmol/L (3 mg/dL).

Haemolytic jaundice – increased bilirubin load for the liver cells

Congenital hyperbilirubinemias – defects in conjugation

Unconjugated

Gilbert’s syndrome, Crigler–Najjar syndrome

Conjugated

Benign recurrent intrahepatic cholestasis, Progressive familial intrahepatic cholestasis (PFIC) syndromes

Cholestatic jaundice, including hepatocellular (parenchymal) liver disease and large duct obstruction.

Differential diagnosis of jaundice

history

clinical features

signs of acute and chronic liver disease:

Hepatomegaly.

A smooth tender liver is seen in hepatitis and with extrahepatic obstruction, but a knobbly irregular liver suggests metastases.

Splenomegaly.

This indicates portal hypertension in patients when signs of chronic liver disease are present. The spleen can also be ‘tipped’ occasionally in viral hepatitis.

Ascites.

This is found in cirrhosis but can also be due to carcinoma (particularly ovarian) and many other causes

palpable gallbladder occurs with a carcinoma of the pancreas obstructing the bile duct

Cold sores are seen with a herpes simplex virus hepatitis.

investigations

ultrasound

size bile duct, level obstruction

liverbiochemistry

AST/ALT

haematology

WBC, mononuclear cells

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Incidence

10 cases per 100000

the fifth most common cause of cancer death in the west

incidence increases with age >60

60% of patients with this condition are male.  adenocarcinoma in type and the large majority are of ductal origin.

Aetiology

risk factors : Smoking is associated with a two-fold increase. Excess intake of alcohol, intake of coffee and use of aspirin, history of diabetes and chronic pancreatitis, 5–10% of patients with pancreatic cancer have a family history of the disease

Clinical picture

Head of pancreas and the ampulla of Vater.

most frequent site for cancer to develop.

present earlier with obstruction to the bile duct as this passes through the head of pancreas giving jaundice
localised lesions painless → pain: tumour progression.

Obstruction of the pancreatic duct → symptomatic episodes of pancreatitis.

Pancreatic damage secondary to duct obstruction is frequently associated with abnormalities of glucose homeostasis.

jaundice with characteristic scratch marks secondary to cholestasis.

Sometimes the gallbladder will be palpable (Courvoisier’s sign).

With metastatic disease, a central abdominal mass may be palpable as well as hepatomegaly.

Carcinoma localised to the body or tail of the pancreas

abdominal pain, anorexia and weight loss

Pain is often dull in character with radiation through/into the back

partial relief of pain by sitting forward.

Bile duct obstruction and jaundice is  late phenomena

investigations

Transabdominal ultrasound

Contrast-enhanced CT scan

Laparoscopy

ERCP(Endoscopic retrograde cholangiopancreatography)

Percutaneous needle biopsy

MRI scanning and endoscopic ultrasound

Several tumour markers

differential diagnosis

IgG4-related autoimmune pancreatitis

management

Endoscopic placement of endoprostheses (stents)

Palliative surgery  in duodenal obstruction

Radiotherapy results have been disappointing

Chemotherapeutic agents

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Classification of pancreatitis

1. Acute pancreatitis: process that occurs on the background of a previously normal pancreas and can return to normal after resolution of the episode

2. Chronic pancreatitis: continuing inflammation with irreversible structural changes

Differentiation between the two can be difficult.

Any of the causes of acute pancreatitis if untreated may result in recurrent episodes classified as acute relapsing pancreatitis

In other cases the recurrent episodes of recurrent pancreatitis may represent exacerbations of an underlying chronic process

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= A syndrome of inflammation of the pancreatic gland initiation by an acute injury

Gallstones and alcohol are the major causes (in Western world)

Severity of pancreatitis may range from mild and self-limiting to extremely severe, with extensive pancreatic and peripancreatic necrosis as well as haemorrhage.

In the most severe cases (10%), mortality is between 40-50%

Pathogenesis

The pancreatic inflammatory response is secondary to the premature exaggerated activation of digestives enzymes within the pancreas itself

An acute rise in intracellular calcium may be the initiating mechanism, leading to early activation of trypsinogen to trypsin and impairment of trypsin degradation by chymotrypsin C

These activated enzymes are responsible for cellular necrosis

In the case of gallstone-related pancreatitis it is believed that stones occlude the pancreatic drainage at the level of the ampulla leading to pancreatic ductular hypertension, which increases cytosolic free ionised calcium

Alcohol interferes with calcium homeostasis in pancreatic acinar cells

Clinical features

Acute pancreatitis is DD in any patient with upper abdominal pain (stabbing)

The pain usually begins in the epigastrium accompanied by nausea and vomiting

As inflammation spreads through the peritoneal cavity, the pain becomes more intense

Involvement of the retroperitoneum frequently leads to back pain

Diagnosis

Blood tests

Serum amylase

Urinary amylase

Serum lipase

C-reactive protein level

Erect chest X-ray

Abdominal ultrasound scan

Contrast-enhanced CT scanning

MRI (MRCP)

ERCP

Assessment

Majority of cases are mild and run a short, self-limiting course

25% run a more complicated course

10% may be life-threatening

haemodynamic instability and multiple organ failure

Early clinical assessment has been shows to have poor sensitivity for predicting a severe attack

Ranson and Glasgow scoring system

Acute physiology and chronic health evaluation (APACHE) score

treatment

Nasogastric suction: prevents abdominal distension and vomitus and hence the risk of pneumonia

Baseline arterial blood gases: key predictive factor for severity of an episode and determine the need for continuous oxygen administration

Prophylactic antibiotics: unknown how useful it is. There is evidence that the beta lactam imipenem reduced the incidence of infected pancreatic necrosis

Analgesia requirements: opiates are the drug of choice for immediate post-presentation pain control.

Feeding: in patients with a severe episode there is little likelihood of oral nutrition for a number of weeks. Total parenteral nutrition is associated with a high risk of infection and has been replaced by enteral nutrition

Anticoagulation: with low molecular weight heparin for DVT prophylaxis

complications

reflection on the systemic inflammatory response, which in turn results in multiple organ failure

After this initial period, the prognosis is mostly related to the extent of pancreatic necrosis

When the damaged area has been walled off and liquefaction has begun and pseudocyst develops

acute sepsis

prognosis

full recovery mild to moderate AP

recurrent episodes

insufficient exocrine and endocrine function in sever AP

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Aetiology

Developed countries: 60-80% alcohol is cause

Other factors: toxic-metabolic, genetic, autoimmune, recurrent acute or severe acute pancreatitis, obstruction and idiopathic

Pathogenesis

An increase in activated trypsin within the pancreas is a common pathway for the development of chronic pancreatitis

result of increased/premature activation of trypsinogen to trypsin or by imapred inactivation/clearance of the activated enzyme of the pancreas

Increased/prolonged intrapancreatic enzyme activity leads to the precipitation of proteins within the duct lumen inthe form of plugs

These form a nidus for calcification and are the cause of ductal obstruction leading to ductal hypertension and further pancreatic damage

Alcohol related chronic pancreatitis

Alcohol impairs calcium regulation leading to increased levels

These promote trypsinogen activation and diminish the inactivation pathway

Alcohol is only one factor which interacts with other environmental/genetic influences

genetics aspects

trypsinogen produced in the pancreas and encoded by the PRSS1 gene --> mutated

SPINK-1 is a specific trypsin inhibitor and is co-secreted with trypsinogen by the acinar cells. Loss of function mutations of SPINK-1 gene

Chymotrypsin C is produced in trace amounts by the acinar cells and has a role in trypsin inactivation. Loss of function mutations of the encoding gene

CFTR mutation → idiopathic chronic pancreatitis

Autoimmune chronic pancreatitis (ACP)

IgG4-related disorders: include autoimmune cholangitis, Reidel’s thyroiditis, aortitis and tubulo-interstitial nephritis.

clinical features

pain, usually epigastric and often radiates through into the back

episodic, with short periods of severe pain, or chronic unremitting Exacerbations

abdominal pain anorexia is common and weight loss may be severe

Exocrine and endocrine insufficiency

Jaundice

investigation

Serum amylase and lipase:  elevated

Faecal elastase: abnormal

Gene mutation analysis

Transabdominal ultrasound scan

Contrast-enhanced spiral CT scan

MRI and MRCP

Endoscopic ultrasound:

Differential diagnosis

Carcinoma of the pancreas

The diagnosis of malignancy should be considered in patients with short history and in whom there is a localised ductular abnormality

treatment

short-term flare-ups of pain a combination of non-steroidal anti-inflammatory drug and an opiate for abdominal pain

pancreatic enzyme supplements steatorrhoea

treat diabetes

complications

Pseudocyst = fluid collection surrounded by granulation tissue (most common structural complication)

Ascites and occasionally pleural effusions

Cystic fibrosis

Increased risk of pancreatic cancer

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Basic characteristics and effect pancreas 

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Basic characteristics and effect pancreas 

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autosomal recessive disorder
CFTR gene --> mutated
affects the cells that produce mucus, sweat and digestive juices.
--> secretions to become sticky and thick. Instead of acting as lubricants, the secretions plug up tubes, ducts and passageways, especially in the lungs and pancreas.

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Exocrine function

Pancreatic acinar cells: responsible for production of digestive enzymes

Amylase, lipase, colipase, phospholipase and proteases (trypsinogen + chymotrypsinogen)

These enzymes are stored within the acinar cell in secretory granules and are released by exocytosis

After a meal, pancreatic exocrine secretion is regulated by cephalic, gastric and intestinal stimuli

Cholecystokinin

Produced in I cells (= specialised gut endocrine cells) of the mucosa of the small intestine

Secreted in response to intraluminal food

CCk acts via receptors on vagal afferent fibres to stimulate pancreatic secretion

Proteases and colipase are secreted as inactive precursors and require duodenal enterokinase to initiate activity

Secretin:

Pancreatic Polypeptide

Released from the islet cells from the pancreas in response to a meal

Has an inhibitory effect upon acinar enzyme secretion both by a local effect and via central receptors

Somatostatin:

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Consists of hormone-producing cells arranged in nests of islets (islets of Lagnerhans)

The hormones produces are secreted directly into the circulation and there is and access to the pancreatic ductular system

Five main types of islet cell corresponding to different secretory components:

1. Beta cell: most common, responsible for insulin production

2. Alpha cell: produces glucagon

3. D cell: produce somatostatin

4. PP cell: produce pancreatic polypeptide

5. Enterochromaffin cell: produce serotonin

Other hormones: gastrin-releasing peptide, neuropeptide Y and galanin → neurotransmitters active in the neuro-gastrointestinal axis

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heterogeneous group of tumours with varying tumour biology and prognosis and 40–50% of the patients present with symptoms related to the substances released from the tumours

Investigation and management

cross-sectional imaging, including CT and MRI scanning. Expression of somatostatin receptors and can be mapped by scintigraphy. Recently, PET scanning with specific isotopes have been introduced.

surgery of the primary lesion

Somatostatin analogues to control hormonal related symptoms and also have a tumour modulating effect.,

Presentation

Endoscopic ultrasound most sensitive means of detecting small tumours. Many of these tumours have somatostatin receptors, and radiolabeled somatostatin analogue scanning provides a means of tumour localization.

Treatment

Surgical resection of the pancreatic lesion is the only potential curative approach

Somatostatin analogues

antiangiogenesis therapy utilising vascular endothelial growth factor (VEGF) antagonists

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Serous cystadenomas

composed of multiple small cystic cavities lined by cuboidal glycogen-rich, mucin-poor cells.

elderly age group, asymptomatic

Malignant transformation in a serous cystadenoma is extremely rare. Larger serous cystadenomas may cause local compressive complications

Mucinous cystadenomas

exclusively found in women in the 5th and 6th decades and are sited in the pancreatic body and tail.

Multilocular cysts are lined by tall mucin-synthesising cells.

20% are malignant at the time of presentation and the majority appear to have a malignant potential. more likely to produce symptoms.

Intraductal papillary mucinous tumour (IPMT)

pancreatic cystic neoplasm that can arise from either the side branches or the main duct.

the majority are found in men 60-70.

pancreatic pain/asymptomatic.

slowly progressive with a significant malignant potential; more so when the main duct is the site of origin.