Typhoid Fever pancreatitis

Typhoid Fever
Typhoid fever is a systemic infection with the bacterium Salmonella enterica serotype typhi. A subset of Salmonella serotypes that includes S. typhi and S. paratyphi causes enteric (typhoid) fever and is restricted to growth in human hosts. Clinically S. typhi > S. paratyphi

Salmonella
Genus enterobacteriaceae

"S. enteritidis" including var. typhimurium, paratyphi & bongori 200 serovarian S. cholerae-suis, 1 serovar S. typhi, 1 serovar

gram-negative bacilli Motil & pathogenic Salmonella can be further divided into serovars based on the detection of three major antigenic determinants:

the somatic O antigen [lipopolysaccharide (LPS) cell-wall components] the surface Vi antigen (restricted to S. typhi and S. paratyphi C), the flagellar H antigen.

Nomenklatur

Epidemiology
Endemic in developing contries Incubation period : 3 d 3 m (1-3 wk) Transmission :
most cases of disease result from ingestion of contaminated food or water anal-oral transmission health care workers

Pathogenesis
The bacteria traverse the gastrointestinal tract, including the acidic environment of the stomach, to colonize the small intestines. Salmonellae cross the intestinal barrier, where phagocytosis by macrophages results in their dissemination throughout the reticuloendothelial system. Once salmonellae reach the small intestine, the bacteria resist a variety of innate immune factors before penetrating the mucus layer. The organisms enter the intestines through phagocytic microfold or M cells overlying the Peyer's patches. Salmonellae (S. typhi or S. paratyphi) undergo phagocytosis by macrophages after crossing the epithelial layer of the small intestine. Once phagocytosed, the bacteria are protected from PMNs) the complement system, and antibodies. After phagocytosis, salmonellae disseminate throughout the body in macrophages via the lymphatics and colonize reticuloendothelial tissues (liver, spleen, lymph nodes, and bone marrow). Signs and symptoms, including fever and abdominal pain, probably result from secretion of cytokines by macrophages when a critical number of organisms have replicated. .

Patogenesis

Patofisiologi

Rose spot

Relative bradicardia

Laboratorium

Widal Test

Treatment

Complications
Complications occur in 10 to 15 percent of patients Gastrointestinal bleeding, intestinal perforation, and typhoid encephalopathy are the most important. Gastrointestinal bleeding is the most common, occurring in up to 10 percent of patients. It results from erosion of a necrotic Peyers patch through the wall of an enteric vessel.

Carrier Typhoid

Typhoid Fever Prevention

Safe water supplies, sanitary disposal of human feces and hygienic food handle are essential steps to Typhoid control.
Sanitation improvements demand high public investments. For this reason, achieving real gains in sanitation coverage has been a challenge in developing countries. Whether a rapid reduction in the incidence of Typhoid could be brought about by mass vaccination has been a matter of discussion. The currently licensed Vi polysaccharide vaccines are not very effective. In Brazil vaccines have not been used so far.

Acute Pancreatitis

Associated Structures of the Gall Bladder and Pancreas

Acute Pancreatitis Epidemiology

Second most common principal inpatient GI diagnosis after cholelithiasis and acute cholecystitis Unreliable data due to misdiagnosis Estimated yearly incidence of 540/100,000 1998 data from the U.S. about pancreatic diseases
327,000 inpatient stays 78,000 outpatient hospital visits 195,000 ER visits 531,000 office visits

Natural History
80% of cases are mild 20% are severe with organ failure and local complications Overall mortality estimates range from 2% to 10% Half of death occur within the first week, perhaps 25% to 33% of deaths occur within the first 48 hours Obese patients have higher rates of local complications, respiratory failure, severe acute pancreatitis and death from sterile necrosis than non-obese patients
Estimated 25-33% mortality

Definition
Acute inflammation of the pancreas Varying degree of regional tissue involvement and remote organ systems Classified as acute unless there is evidence of chronic pancreatitis, otherwise considered as exacerbation of

Pathology
Initial injury to peripheral acinar cells, fat necrosis and autodigestion Interstitial (edematous) pancreatitis:
Interstitial edema associated with inflammatory cells in the parenchyma Parenchymal necrosis is microscopic

Necrotizing pancreatitis
Focal macroscopic or diffuse necrosis Hemorrhage, vascular thrombosis Involvement of the main pancreatic duct

Pathogenesis of Acute Pancreatitis

Trypsinogen to trypsin conversion in acinar cells overwhelms neutralization mechanisms Proenzymes (trypsinogen, elastase, phospholipase A2 (PLA2) and carboxypeptidase) are activated by trypsin Activation of complement and

Etiologies of Acute Pancreatitis

Obstructive Toxic Metabolic Infectious Vascular Trauma Iatrogenic Hereditary Controversial etiologies

Obstructive causes of AP
Gallstones/microlithiasis Tumors Parasites (those causing obstruction, e.g. Ascaris, Clonorchis) Duodenal diverticula Annular pancreas Choledochocele Celiac sprue? (chronic duodenal inflammation causing ampullary stenosis)

Toxic and Metabolic Etiologies

Toxic
Ethanol Methyl alcohol Scorpion venom (hyperstimulation of pancreas) Organophosphate insecticides (hyperstimulation of pancreas) Drugs

Metabolic
Hypertriglyceridemia Hypercalcemia

Other Causes
Cardiovascular
Small vessel vasculitis Emboli to pancreatic vessels Hypotension

Blunt and penetrating abdominal traumas Iatrogenic

ERCP Surgery

Gallstone/Biliary Pancreatitis
40% of all cases of AP Risk of AP due to existing gallstones is greater in men, but overall incidence is lower as gallstones are more common in women Small stones (< 5 mm) are more likely to cause pancreatitis

Biliary Sludge
Viscous suspension of gallbladder bile that may contain tiny stones (< 3 mm) Usually composed of cholesterol monohydrate crystals, but also occurs with ceftriaxone-bile complexes Appears as a mobile, low-amplitude echo without shadow Biliary sludge often develops in acute pancreatitis

Alcohol
Causes 30% of cases Most but not all patients also have some degree of underlying chronic pancreatitis Proposed mechanisms:
Sphincter of Oddi relaxation & duodenal reflux Increased pancreatic duct permeability Sudden release of pancreatic enzymes with inappropriate activation Increased protein concentration in pancreatic juice leading to obstruction

Hypertriglyceridemia
Third most common identifiable cause of AP Serum triglycerides > 1000 mg/dL Median serum TG concentration ~ 3-4K Mechanism?
Possibly, release of free fatty acids may cause pancreatic acinar

Hypertriglyceridemia
Associated conditions in adults
Diabetes mellitus Alcohol abuse (chicken or the egg?) Obesity Hypothyroidism Pregnancy Estrogen therapy Types I & V hyperlipoproteinemia

Hypercalcemia
Rare, proposed mechanism is due to deposition of calcium in the pancreatic duct with activation of trypsinogen in the pancreatic parenchyma Chronic hypercalcemia less likely to induce pancreatitis than acute increases (animal data) Hyperparathyroidism causes < 0.5% of all cases of acute pancreatitis Incidence of acute pancreatitis in hyperparathyroidism is reportedly 02%1.5% Rarely after metastatic cancer with bone involvement, TPN, sarcoidosis, vitamin D toxicity and following parenteral

Tumors
Probably cause AP due to obstruction of the pancreatic duct Usually in older patients Most common with intraductal papillary mucinous neoplasm/tumor (IPMN/IPMT) of the pancreas Also possible with ampullary neoplasms Less commonly due to pancreatic adenocarcinoma

Drugs General Considerations

Over 80 drugs implicated based on unconvincing anecdotal reports Usually mild and self-limited after stopping drug Reliable causative etiology requires:
Exclusion of other etiologies Appropriate interval (usually 4-8 weeks) since initiation of therapy Clear mechanism of drug-induced pancreatitis Reproducible recurrence of pancreatitis

Drugs Implicated

-Methyldopa Mesalamine Cimetidine Cytosine arabinoside Dexamethasone Ethinylestradiol/ lynestrenol Furosemide Isoniazid 6-Meraptopurine Metronidazole Norethindrone/mes tranol

Pentamidine Perindopril Pravastatin Procainamide Stibogluconate Sulfamethizole Sulfasalazine Sulindac Tetracycline TMP/SMX Didanosine Valproic acid

Potential Mechanisms
Hypersensitivity reactions
Usually after 4-8 weeks of starting medication Not dose-related On rechallenge, recurrent pancreatitis occurs after a few days E.g. 6-MP/azathioprine, aminosalicylates, metronidazole, tetracycline

Potential Mechanisms (Contd)

Accumulation of toxic metabolites
Onset typically occurs after several months E.g. valproic acid, didanosine

Hypertriglyceridemia
Thiazides, tamoxifen, isotretinoin

Intrinsic toxicity
Pancreatitis can occur with

Diagnosis of AP
Clinical findings Laboratory findings Radiological findings

Clinical Findings
Usually acute onset of severe pain Epigastric, upper quadrants Radiation to back and chest (DDx myocardial ischemia) Nausea, vomiting, hematemesis Bowel obstruction Fever, tachypnea, shock Ecchymoses on the flanks (Turners sign) Periumbilical ecchymosis (Cullens

Laboratory findings
2-3 fold elevations of pancreatic enzymes amylase and/or lipase Amylase
Cheap, fast and widely available Not 100% sensitive or specific (normal values in mild attacks, in the setting of chronic pancreatitis or even with fatal pancreatitis have been reported) False positive (as far as AP Dx is concerned) with:
Macroamylasemia (e.g. IG-bound amylase not cleared by kidneys) Parotitis (can also be EtOH induced, look for hamster cheeks!) Salpingitis/ectopic pregnancy Bowel obstruction and perforation

Lipase
Sensitivity similar to amylase (85%-100%) Probably more specific (all pancreatic except a small amount of gastric lipase) Usually remains elevated longer than amylase False positive values in:
Renal insufficiency Macrolipasemia

Other Pancreatic Enzymes

Generally speaking, no significant clinical advantage over routine tests due to:
Similar dynamics Expense Unavailability

Phospholipase A2 Trypsin Caboxypeptidase A Colipase Elastase Ribonuclease

Trypsin Activation Peptide (TAP)

Other Lab Findings

Nonspecific findings include
Leukocytosis LFT abnormalities CRP and other acute reactants Serum triglycerides Azotemia Hyperglycemia

Radiological Findings
Plain Films:
Localized segment of small intestine (sentinel loop) Generalize ileus Calcifications (stones, or pancreas with chronic calcific pancreatitis) Pneumobilia following stone passage and/or bilioenteric fistula formation Severe ascites Retroperitoneal gas (pancreatic abscess) 30% with CXR abnormalities (elevated hemidiaphragm, pleural effusion, basal

CT and US
Cross-sectional imaging with more specific pancreatic changes (i.v. contrast is needed for detecting necrosis and tumors) US may show biliary dilation, stones, pancreatic calcifications, hypoechoic appearance of the pancreas with edema, pseudocysts and peripancreatic fluid collections,

Differential Diagnosis
Biliary pain and acute cholecystitis Epigastric distress syndrome/nonulcer dyspepsia Peptic ulcer disease and perforated hollow viscus Small bowel obstruction Inferior myocardial infarction Aortic dissection Ruptured ectopic pregnancy Acute appendicitis

Range of Severity
Mild
Minimal or no organ dysfunction Full recovery without complications

Severe

Local complications Organ failure death

Predictors of Severity
Ransons Score 2: Mortality 2.5%* Ransons Score 3: Mortality 62%* Limitations of Ransons Score:
Cumbersome Takes 48 hours to compute Not validated beyond 48 hours * Obtained of within the first 48 hours Cutoff of 3 has sensitivity 40%-

Ransons Criteria
Parameter On Admission Age (years) WBC (cells/mm3) Glucose (mg/dL) LDH (IU/L) AST (U/L) During initial 48h in hct (%) BUN (mg/dL) Calcium (mg/dL) pO2 (mm Hg) Base deficit (mEq/L) Fluid seq. estimate (L) 1974 (Alcoholic) >55 >16,000 >200 >350 >250 >10 >5 <8 <60 >4 >6 1982 (Biliary) >70 > 18,000 >220 >400 >250 >10 >2 <8 NA >5 >4

Atlanta Criteria for Severe AP

ORGAN FAILURE

Shock
Pulmonary insufficiency Renal failure GI bleeding Necrosis Abscess Pseudocyst

SBP < 90 mm Hg
pO2 60 mm Hg Serum creatinine > 2 mg/dL >500 mL/24 hr

LOCAL COMPLICATIONS

UNFAVORABLE EARLY PROGNOSTIC SIGNS

3 Ransons criteria APACHE II score 8

Approach to Patient
Triage
Prognosis Placement

Etiology
Could affect the acute management

Supportive care
I.v. fluid resuscitation Nutritional support Analgesia

Further care
Observation for early detection of potential complications Treatment of complication Nutritional support (10% rate of TPN line infections in patients with severe pancreatitis)

Nutritional Support
TPN disadvantages
Expensive High complication rate Generally associated with higher morbidity and longer lengths of stay than enteral feeding via nasoenteric tubes In mild to moderate AP, enteral feeding was started within 48 hours of admission and was associated with faster improvement and shorter LOS than TPN In severe/necrotizing pancreatitis, LOS,

Specific Management
Based on (suspected) etiology Includes emergent and elective items Diagnostic strategy incorporates potential probabilities and associated risks of diagnostic tests Therapeutic strategy incorporates potential