STUDY - Technical - New Dacian's Medicine
Jaundice
(3)
Translation Draft
I'm going to start this post by addressing jaundice evaluation. The first task in the evaluation of jaundice is to determine whether bilirubinemia is due to hemolysis or a hepatobiliary disease. This differentiation is most easily achieved by measuring fractions of direct and indirect bilirubin. A predominantly unconjugated hyperbilirubinemia indicates a hemolytic disorder due to accelerated intravascular destruction of erythrocytes or resorption of a voluminous hematoma.
Exceptions to this rule are Gilbert syndrome, the other rare, hereditary disorders of glucuronyl-transferase and end-stage liver failure. Jaundice associated with predominant bilirubinemia (more than 50%) usually results from one of three groups of conditions: hepatocellular diseases, intrahepatic biliary obstruction ("cholestasis") and intrahepatic biliary obstruction. A first goal is to determine which category of disease explains the patient's jaundice.
Essential for this determination is careful clinical evaluation, including disease history, physical examination, basic liver function tests and a complete haemoleukogram. Using these simple tools, experienced clinicians can determine the overall nature of jaundice in most cases. The most important, however, is that the results of the clinical evaluation direct the doctor towards a logical progression of imaging investigations, serological tests and pathological evaluation. Initial clinical evaluation should be focused on the characteristics of the patient's disease, which distinguish between hepatocellular disease, intrahepatic cholestasis and extrahepatic biliary obstruction.
From a historical point of view, the history assessment should include determining the duration of symptoms, the presence and character of abdominal pain, fever or other symptoms of active inflammation and changes in appetite, body weight and intestinal transit. Special attention should be paid to a history of blood transfusions, intravenous drug use, promiscuous sexual activity and ethanol use. A history of drug use should be made, especially drugs known to cause cholestasis, such as anabolic steroids and chlorpromazine, or hepatocellular necrosis, such as acetaminophen or isoniazide. A history of arthralgia may suggest acute viral hepatitis.
Viral diseases should also be evoked in patients with a history of travel to countries with weak medical system, endemic to enteral-transmitted hepatitis E or where parenterally transmitted hepatitis B and C viruses are widespread. Pruritus is most commonly associated with chronic cholestasis, as a result of either extrahepatic obstruction or cholestatic liver disease such as sclerosing cholangitis or primitive bile cirrhosis.
On the contrary, achole lones occur more frequently in patients with extrahepatic biliary obstruction due to a tumor, choledocian lithiasis or secondary to a congenital biliary abnormality, such as inflamed choledocian cyst. The presence of acholic and hem-positive stools (silver stools) should suggest a tumor of the distal bile tract such as ampulary carcinoma, periampulary or cholangiocarcinoma. This combination can also be found in patients with pancreatic carcinoma that penetrates the bile or duodenum pathway.
Jaundice, in the case of previous biliary surgery, may suggest recurrent or recurrent lithiasis disease, biliary stricture or recurrent obstruction due to a growing tumor. Finally, a pre-existing or underlying condition that predisposes to hepatobiliary diseases should be considered. For example, inflammatory bowel disease, especially ulcerative colitis, may be associated with sclerosing colangitis. Pregnancy predisposes to cholestasis, steatosis and acute liver failure. Right heart failure can cause hepatic congestion and cholestasis, and septicaemia can cause selective disruption of bilirubin transport or generalized intrahepatic cholestasis.
Physical examination is also important to direct further evaluation. Excoriations suggest long-term cholestasis or high-grade biliary obstruction, and a greenish tinge of jaundice is associated with very serious or long-evolving liver disease, such as biliary cirrhosis, sclerosing cholangitis, severe chronic hepatitis or long-evolving malignant obstruction. Fever and epigastric or right hypochondrium sensitivity are commonly associated with choledoc lithiasis and cholangitis or cholecystitis.
On the contrary, malignant biliary obstruction usually presents as painless jaundice. An enlarged, sensitive liver suggests acute liver inflammation or a rapidly enlarged liver tumor, while a palpable gallbladder suggests distal bile obstruction through the malignant tumor. The presence of splenomegalia may provide an indication for portal hypertension due to active chronic hepatitis, severe or acute viral alcoholic hepatitis or cirrhosis.
Cirosis is also associated with a hyperestrogenic status that can be reflected in gynecomastia, testicular atrophy or star angiomas. Testicular atrophy can be very pronounced in cirrhosis due to alcoholic liver disease or hemochromatosis. Palmar erythema, facial telangiectasis and Dupuytren retraceability are also associated with cirrhosis, especially as a result of chronic ethanol ingestion. Weight loss or lymphadenopathy suggests neoplasm and, in the presence of splenomegaly, these signs may point to a pancreatic tumor that obstructs the splenic vein or widely disseminated metastatic lymphoma.
In patients whose history of the disease or physical examination suggests neoplasia, special attention should be paid to clinical findings that evoke primary tumours, including hem-positive stools, abdominal or breast tumors, thyroid nodules and supralavilular lymphadenopathy. Physical signs associated with specific liver disease include dilated throat veins and hepatojugular reflux (right heart failure), xantomas (primitive bile cirrhosis) and Kayser-Fleischer rings (Wilson's disease).
The initial laboratory assessment should be centred on the fractionation of serum bilirubin. Predominantly unconjugated (indirect) hyperbilirubinemia should turn attention to a hemolytic condition, e.g. autoimmune or microangiopathic hemolytic anaemia, ineffective erythropoiesis or resorption of a voluminous hematoma. The most common cause of slight growth of the unconjugated fraction, however, is Gilbert syndrome, a hereditary condition, the result of a mild deficiency of glucuronyl-hepatic transferase.
Individuals with Gilbert syndrome exhibit variable increases in circulating unconjugated bilirubin, especially in combination with physical stress, fever, intercurrent infection or surgery, fasting or massive ethanol ingestion. This mild metabolic abnormality does not produce symptoms other than jaundice and is not associated with enzymatic liver abnormalities or long-term adverse effects. Conjugated (direct) hyperbilirubinemia usually results from hepatocellular or cholestatic liver disease or extrahepatic bile obstructions.
Since the activity of liver glucuronyl-transferase is normally present in abundance, adequate bilirubin-glucuronide formation can occur even in serious liver disease. in patients with predominantly conjugated hyperbilirubinemia, the presence and nature of liver enzyme abnormalities usually provide important clues about the nature of the underlying process. Conjugated hyperbilirubinemia without enzymatic liver abnormalities is relatively unusual, but may occur in pregnancy, septicaemia or after recent surgery.
Isolated conjugate hyperbilirubinemia is the primary manifestation in two hereditary disorders, rotor and Dubin-Johnson syndromes, and can also be found in some patients with benign recurrent intrahepatic cholestasis syndrome. The disproportionate increase in aminotransferases compared to other liver enzymes suggests hepatocellular lesions, most commonly found in toxic, viral or ischemic hepatitis, while significant increases in alkaline phosphatase, 5'-nutleotidase and/ or gamma-glutamyl-transpeptidase are more suggestive for intrahepatic cholestasis or extrahepatic obstruction.
Although these patterns are not invariably diagnosed, they are useful in directing further evaluation. Patients with a clinical evaluation and laboratory results suggestive of a hepatocellular disease should be examined for signs of viral hepatitis, drug toxicity, hepatic congestion, such as right ventricular insufficiency or acute obstruction of the liver veins, or ischemic hepatitis.
In an appropriate clinical setting, serological studies are extremely useful in establishing or excluding the diagnosis of hepatitis A, acute and chronic hepatitis B, hepatitis C, D and E and hepatitis caused by cytomegal virus (CMV) or Epstein-Barr virus. Common causes of toxic hepatitis include acetaminophen, isoniazide and halogenated anesthetic agents. Patients with alcoholic liver disease are highly susceptible to acetaaminophen toxicity, which in these individuals may occur after therapeutic doses.
For patients with probable hepatocellular disorders, liver biopsy may provide important diagnostic and prognostic information. Percutaneous, transjugular or laparoscopic biopsy results may also provide important information for optimal therapy. The role of hepatobiliary imaging techniques in these patients is less well defined. In some cases, the identification of focal lesions by computed tomography (CT), abdominal ultrasound, or nuclear magnetic resonance (NMR) may increase the diagnostic accuracy of liver biopsy.
These imaging techniques can also guide the diagnosis by suggesting the presence of fatty liver deposits, cirrhosis or excessive liver deposits of iron from hemochromatosis. Ultrasound is a very sensitive way to detect ascites. Combined with Doppler flow analysis, it can also determine the permeability and direction of flow in the portal and liver veins, frequently allowing noninvasive diagnosis of portal vein thrombosis and Budd-Chiari syndrome.
There's something to be done about hepatobiliary imaging techniques. For patients whose clinical and hepatic chemical evaluation suggests cholestasis or extrahepatic biliary obstruction, bile imaging techniques are an important early diagnostic tool to differentiate intrahepatic causes from extrahepatic obstruction. Both ultrasound and TC detect dilated extrahepatic bile ducts with high sensitivity. In the absence of hepatobiliary surgical history, the specificity of these methods for identifying dilated extrahepatic ducts far exceeds 90%.
Both techniques are sensitive indicators of intrahepatic, portal and pancreatic masses, and any can be effective in differentiating bile obstruction from tumors or blocked calculations. In addition, endoscopy is an extremely effective means of detecting stones in the gallbladder and is somewhat more sensitive than TC. These imaging techniques are considerably less sensitive in detecting choledocolithiasis. None of these techniques manages to detect about 40% of intraductal calculations, although selected studies suggest that TC is slightly better at detecting stones in undilated ducts.
In patients with clinical and radiographic signs of extrahepatic biliary obstruction, further evaluation should be directed towards determining the cause of the obstruction and achieving rapid improvement. Masses identified by transabdominal or endoscopic ultrasound, TC or MRI are usually accessible to radiographic or endoscopically directed percutaneous biopsy. Better definition and improvement in extrahepatic bile obstruction can often be achieved through percutaneous or endoscopic colangiography. In the hands of experienced practitioners, dilated bile ducts can be accessed percutaneously in more than 90% of patients and up to 70% in undilated ducts. Percutaneous transhepatic colangiography (CTP) may be particularly useful for visualization and drainage in patients with bile obstruction above the bifurcation of the common bile duct and in patients whose obstruction cannot be improved during endoscopic colangiography.
The collection of bile for cytological analysis may also allow the identification of obstructive lesion. Retrograde endoscopic cholangiopancreatography (CPER) is frequently the preferred technique for the diagnosis and treatment of distal bile obstructions. In addition to cholangiography, CPER offers the opportunity to inspect and biopsy the Vater ampula and surrounding duodenum (frequent localizations of tumors obstructing the bile ducts), visualization of pancreatic ducts to detect signs of lithiasis of pancreatic ducts or small pancreatic tumors and direct biopsy of the bile ductal epithelium and pancreatic head. Both CTP and CPER can achieve improvement of neoplastic obstruction and dissolution or fragmentation of ductal calculations. CPER also offers the possibility of long-term improvement of lithiasis disease through endoscopic papillarydisease and is the preferred approach of the remaining intraductal calculations after surgical or laparoscopic cholecystectomy.
For patients with clinical signs of cholestasis who have normal-calibre ducts, attention should be focused on intrahepatic cholestasis caused by primitive bile cirrhosis, drugs or toxins (including ethanol) and extrahepatic obstruction without ductal dilation, which may be caused by primary sclerosing cholangitis, primitive bile cirrhosis or intrahepatic arterial chemotherapy and is occasionally found in patients with cholangiocarcinoma. A similar cholestatic process, called missing bile duct syndrome (SDBD), may occur as a result of liver transplant rejection, AIDS, VCM infection and irradiation disease.
SDBD is rarely associated with Hodgkin's disease and sarcoidosis and may develop after treatment with flucloxaciline, anticonvulsants and other medications. If the clinical picture is more suggestive for cholestasis or biliary cirrhosis, liver biopsy may provide the most direct route to diagnosis. On the contrary, cholangiography with cytological analysis of bile and/ or biopsy of the ductal epithelium is indicated in patients whose picture suggests extrahepatic obstruction, such as patients with jaundice and undilated ducts, under conditions of weight loss, adenopathy or inflammatory bowel disease.
I'm done! Tomorrow we'll discuss abdominal distension and ascites.
I'm going to start this post by addressing jaundice evaluation. The first task in the evaluation of jaundice is to determine whether bilirubinemia is due to hemolysis or a hepatobiliary disease. This differentiation is most easily achieved by measuring fractions of direct and indirect bilirubin. A predominantly unconjugated hyperbilirubinemia indicates a hemolytic disorder due to accelerated intravascular destruction of erythrocytes or resorption of a voluminous hematoma.
Exceptions to this rule are Gilbert syndrome, the other rare, hereditary disorders of glucuronyl-transferase and end-stage liver failure. Jaundice associated with predominant bilirubinemia (more than 50%) usually results from one of three groups of conditions: hepatocellular diseases, intrahepatic biliary obstruction ("cholestasis") and intrahepatic biliary obstruction. A first goal is to determine which category of disease explains the patient's jaundice.
Essential for this determination is careful clinical evaluation, including disease history, physical examination, basic liver function tests and a complete haemoleukogram. Using these simple tools, experienced clinicians can determine the overall nature of jaundice in most cases. The most important, however, is that the results of the clinical evaluation direct the doctor towards a logical progression of imaging investigations, serological tests and pathological evaluation. Initial clinical evaluation should be focused on the characteristics of the patient's disease, which distinguish between hepatocellular disease, intrahepatic cholestasis and extrahepatic biliary obstruction.
From a historical point of view, the history assessment should include determining the duration of symptoms, the presence and character of abdominal pain, fever or other symptoms of active inflammation and changes in appetite, body weight and intestinal transit. Special attention should be paid to a history of blood transfusions, intravenous drug use, promiscuous sexual activity and ethanol use. A history of drug use should be made, especially drugs known to cause cholestasis, such as anabolic steroids and chlorpromazine, or hepatocellular necrosis, such as acetaminophen or isoniazide. A history of arthralgia may suggest acute viral hepatitis.
Viral diseases should also be evoked in patients with a history of travel to countries with weak medical system, endemic to enteral-transmitted hepatitis E or where parenterally transmitted hepatitis B and C viruses are widespread. Pruritus is most commonly associated with chronic cholestasis, as a result of either extrahepatic obstruction or cholestatic liver disease such as sclerosing cholangitis or primitive bile cirrhosis.
On the contrary, achole lones occur more frequently in patients with extrahepatic biliary obstruction due to a tumor, choledocian lithiasis or secondary to a congenital biliary abnormality, such as inflamed choledocian cyst. The presence of acholic and hem-positive stools (silver stools) should suggest a tumor of the distal bile tract such as ampulary carcinoma, periampulary or cholangiocarcinoma. This combination can also be found in patients with pancreatic carcinoma that penetrates the bile or duodenum pathway.
Jaundice, in the case of previous biliary surgery, may suggest recurrent or recurrent lithiasis disease, biliary stricture or recurrent obstruction due to a growing tumor. Finally, a pre-existing or underlying condition that predisposes to hepatobiliary diseases should be considered. For example, inflammatory bowel disease, especially ulcerative colitis, may be associated with sclerosing colangitis. Pregnancy predisposes to cholestasis, steatosis and acute liver failure. Right heart failure can cause hepatic congestion and cholestasis, and septicaemia can cause selective disruption of bilirubin transport or generalized intrahepatic cholestasis.
Physical examination is also important to direct further evaluation. Excoriations suggest long-term cholestasis or high-grade biliary obstruction, and a greenish tinge of jaundice is associated with very serious or long-evolving liver disease, such as biliary cirrhosis, sclerosing cholangitis, severe chronic hepatitis or long-evolving malignant obstruction. Fever and epigastric or right hypochondrium sensitivity are commonly associated with choledoc lithiasis and cholangitis or cholecystitis.
On the contrary, malignant biliary obstruction usually presents as painless jaundice. An enlarged, sensitive liver suggests acute liver inflammation or a rapidly enlarged liver tumor, while a palpable gallbladder suggests distal bile obstruction through the malignant tumor. The presence of splenomegalia may provide an indication for portal hypertension due to active chronic hepatitis, severe or acute viral alcoholic hepatitis or cirrhosis.
Cirosis is also associated with a hyperestrogenic status that can be reflected in gynecomastia, testicular atrophy or star angiomas. Testicular atrophy can be very pronounced in cirrhosis due to alcoholic liver disease or hemochromatosis. Palmar erythema, facial telangiectasis and Dupuytren retraceability are also associated with cirrhosis, especially as a result of chronic ethanol ingestion. Weight loss or lymphadenopathy suggests neoplasm and, in the presence of splenomegaly, these signs may point to a pancreatic tumor that obstructs the splenic vein or widely disseminated metastatic lymphoma.
In patients whose history of the disease or physical examination suggests neoplasia, special attention should be paid to clinical findings that evoke primary tumours, including hem-positive stools, abdominal or breast tumors, thyroid nodules and supralavilular lymphadenopathy. Physical signs associated with specific liver disease include dilated throat veins and hepatojugular reflux (right heart failure), xantomas (primitive bile cirrhosis) and Kayser-Fleischer rings (Wilson's disease).
The initial laboratory assessment should be centred on the fractionation of serum bilirubin. Predominantly unconjugated (indirect) hyperbilirubinemia should turn attention to a hemolytic condition, e.g. autoimmune or microangiopathic hemolytic anaemia, ineffective erythropoiesis or resorption of a voluminous hematoma. The most common cause of slight growth of the unconjugated fraction, however, is Gilbert syndrome, a hereditary condition, the result of a mild deficiency of glucuronyl-hepatic transferase.
Individuals with Gilbert syndrome exhibit variable increases in circulating unconjugated bilirubin, especially in combination with physical stress, fever, intercurrent infection or surgery, fasting or massive ethanol ingestion. This mild metabolic abnormality does not produce symptoms other than jaundice and is not associated with enzymatic liver abnormalities or long-term adverse effects. Conjugated (direct) hyperbilirubinemia usually results from hepatocellular or cholestatic liver disease or extrahepatic bile obstructions.
Since the activity of liver glucuronyl-transferase is normally present in abundance, adequate bilirubin-glucuronide formation can occur even in serious liver disease. in patients with predominantly conjugated hyperbilirubinemia, the presence and nature of liver enzyme abnormalities usually provide important clues about the nature of the underlying process. Conjugated hyperbilirubinemia without enzymatic liver abnormalities is relatively unusual, but may occur in pregnancy, septicaemia or after recent surgery.
Isolated conjugate hyperbilirubinemia is the primary manifestation in two hereditary disorders, rotor and Dubin-Johnson syndromes, and can also be found in some patients with benign recurrent intrahepatic cholestasis syndrome. The disproportionate increase in aminotransferases compared to other liver enzymes suggests hepatocellular lesions, most commonly found in toxic, viral or ischemic hepatitis, while significant increases in alkaline phosphatase, 5'-nutleotidase and/ or gamma-glutamyl-transpeptidase are more suggestive for intrahepatic cholestasis or extrahepatic obstruction.
Although these patterns are not invariably diagnosed, they are useful in directing further evaluation. Patients with a clinical evaluation and laboratory results suggestive of a hepatocellular disease should be examined for signs of viral hepatitis, drug toxicity, hepatic congestion, such as right ventricular insufficiency or acute obstruction of the liver veins, or ischemic hepatitis.
In an appropriate clinical setting, serological studies are extremely useful in establishing or excluding the diagnosis of hepatitis A, acute and chronic hepatitis B, hepatitis C, D and E and hepatitis caused by cytomegal virus (CMV) or Epstein-Barr virus. Common causes of toxic hepatitis include acetaminophen, isoniazide and halogenated anesthetic agents. Patients with alcoholic liver disease are highly susceptible to acetaaminophen toxicity, which in these individuals may occur after therapeutic doses.
For patients with probable hepatocellular disorders, liver biopsy may provide important diagnostic and prognostic information. Percutaneous, transjugular or laparoscopic biopsy results may also provide important information for optimal therapy. The role of hepatobiliary imaging techniques in these patients is less well defined. In some cases, the identification of focal lesions by computed tomography (CT), abdominal ultrasound, or nuclear magnetic resonance (NMR) may increase the diagnostic accuracy of liver biopsy.
These imaging techniques can also guide the diagnosis by suggesting the presence of fatty liver deposits, cirrhosis or excessive liver deposits of iron from hemochromatosis. Ultrasound is a very sensitive way to detect ascites. Combined with Doppler flow analysis, it can also determine the permeability and direction of flow in the portal and liver veins, frequently allowing noninvasive diagnosis of portal vein thrombosis and Budd-Chiari syndrome.
There's something to be done about hepatobiliary imaging techniques. For patients whose clinical and hepatic chemical evaluation suggests cholestasis or extrahepatic biliary obstruction, bile imaging techniques are an important early diagnostic tool to differentiate intrahepatic causes from extrahepatic obstruction. Both ultrasound and TC detect dilated extrahepatic bile ducts with high sensitivity. In the absence of hepatobiliary surgical history, the specificity of these methods for identifying dilated extrahepatic ducts far exceeds 90%.
Both techniques are sensitive indicators of intrahepatic, portal and pancreatic masses, and any can be effective in differentiating bile obstruction from tumors or blocked calculations. In addition, endoscopy is an extremely effective means of detecting stones in the gallbladder and is somewhat more sensitive than TC. These imaging techniques are considerably less sensitive in detecting choledocolithiasis. None of these techniques manages to detect about 40% of intraductal calculations, although selected studies suggest that TC is slightly better at detecting stones in undilated ducts.
In patients with clinical and radiographic signs of extrahepatic biliary obstruction, further evaluation should be directed towards determining the cause of the obstruction and achieving rapid improvement. Masses identified by transabdominal or endoscopic ultrasound, TC or MRI are usually accessible to radiographic or endoscopically directed percutaneous biopsy. Better definition and improvement in extrahepatic bile obstruction can often be achieved through percutaneous or endoscopic colangiography. In the hands of experienced practitioners, dilated bile ducts can be accessed percutaneously in more than 90% of patients and up to 70% in undilated ducts. Percutaneous transhepatic colangiography (CTP) may be particularly useful for visualization and drainage in patients with bile obstruction above the bifurcation of the common bile duct and in patients whose obstruction cannot be improved during endoscopic colangiography.
The collection of bile for cytological analysis may also allow the identification of obstructive lesion. Retrograde endoscopic cholangiopancreatography (CPER) is frequently the preferred technique for the diagnosis and treatment of distal bile obstructions. In addition to cholangiography, CPER offers the opportunity to inspect and biopsy the Vater ampula and surrounding duodenum (frequent localizations of tumors obstructing the bile ducts), visualization of pancreatic ducts to detect signs of lithiasis of pancreatic ducts or small pancreatic tumors and direct biopsy of the bile ductal epithelium and pancreatic head. Both CTP and CPER can achieve improvement of neoplastic obstruction and dissolution or fragmentation of ductal calculations. CPER also offers the possibility of long-term improvement of lithiasis disease through endoscopic papillarydisease and is the preferred approach of the remaining intraductal calculations after surgical or laparoscopic cholecystectomy.
For patients with clinical signs of cholestasis who have normal-calibre ducts, attention should be focused on intrahepatic cholestasis caused by primitive bile cirrhosis, drugs or toxins (including ethanol) and extrahepatic obstruction without ductal dilation, which may be caused by primary sclerosing cholangitis, primitive bile cirrhosis or intrahepatic arterial chemotherapy and is occasionally found in patients with cholangiocarcinoma. A similar cholestatic process, called missing bile duct syndrome (SDBD), may occur as a result of liver transplant rejection, AIDS, VCM infection and irradiation disease.
SDBD is rarely associated with Hodgkin's disease and sarcoidosis and may develop after treatment with flucloxaciline, anticonvulsants and other medications. If the clinical picture is more suggestive for cholestasis or biliary cirrhosis, liver biopsy may provide the most direct route to diagnosis. On the contrary, cholangiography with cytological analysis of bile and/ or biopsy of the ductal epithelium is indicated in patients whose picture suggests extrahepatic obstruction, such as patients with jaundice and undilated ducts, under conditions of weight loss, adenopathy or inflammatory bowel disease.
I'm done! Tomorrow we'll discuss abdominal distension and ascites.
A great and peaceful day,
understanding, love and gratitude!
Dorin, Merticaru