Let’s See A Case Scenario

A Case History

A patient named M, 55 years old from Mymensingh admitted in Medicine Unit VIII with the complaints of drowsiness for 5 hours, generalised weakness, nausea, loss of appetite and bodyache for about 1-2 years which has gradually worsen in the last 1 month. She has been complaining gradual weakness in walking and for the last couple of weeks she is unable to walk. In the past couple of months she complained constipation for several episodes which was not

associated with any rectal bleeding or pain during defecation. She has lost about 5 Kg weight in past 2 months. She gave no history of polyuria and polydipsia. She is normotensive, non diabetic, non asthmatic and gave no history of contact with tuberculosis. On examination she anxious, a bit dehydrated, pulse being 112 b/min,BP-120/80mmHg, RR- 18 breaths/min, Temp- 99 degree F. There was mass on the right side of neck 3 cm x 2 cm in size, nodular, firm in consistency & non tender and there was bowing of the tibia.

Investigations•Her CBC showed Hb% 12.1 mg/dl, RBC-

3.94 x 10^12/L, WBC- Neutrophilic Leucocytosis, Platelet- 385 x 10^9/L, ESR- 85 mm in 1st hour.

•Serum Creatinine- 1.72 mg/dl•Serum FT3-1.81 pg/ml ,FT4- 0.93ng/dl,

TSH-2.18 microIU/ml•SGPT- 15 U/L, ALP- 213 U/L•Serum Calcium- 16.0 mg/dl•Spot Urine Calcium- 21.9 mg/dl•Serum Inorganic PO4- 3.8 mg/dl

• Serum PTH- 1450.8 pg/ml• BMD- Marked osteoporosis of lumber spine (-

5.8) and left femoral neck (-5.5).• USG of neck- Enlargement of the both lobes of

thyroid glands with few small nodules in the right lobe and suspected large parathyroid mass.

• CT features consistent with multi-nodular goitre involving right thyroid lobe causing compression and leftward displacement of adjacent trachea.

• FNAC from Parathyroid mass- Suggestive of Parathyroid adenoma.

Approach to a Patient with Hypercalcaemia

Presented By:Dr. Md. Asif HossainK-66 BatchDhaka Medical College Hospital

Regarding Calcium •Calcium is one of the most abundant

mineral in the human body and it has many important biological functions

•1000-2000 g of Ca is present normally in human body

•99% - in the skeleton •Remaining amount -distributed in the ECF

and other soft tissues•Normal range 2.1–2.6 mmol/L (8.5-10.5

mg/dl)

•In Blood , total Ca conc. is normally 8.5-10.5 mg/dl, of which approximately 50% is ionized

•Remainder is bound ionically to negatively charged proteins- Predominantly albumin (40%) and immunoglobulins or lossely complexed with PO4 , citrate ,SO4 and other anions

Calcium homeostasis •Total body : 1 Kg

▫99% bone▫0.9% intracellular▫0.1% ECF

•In blood▫40-45% mostly albumin▫40-50% free or ionized ▫10-15% small anions : phosphate and citrate

Ionized Ca is Physiologically important.

• Dietary intake of Ca 400-1500 mg/day• Daily intestinal absorption of Ca 200-400 mg/day• Renal excretion regulated by conc of ionised Ca in

blood• Approx 8-10 g/day of Ca filtered by the glomeruli of

which only 2-3% appears in urine (200mg)• 65% absorbed in PCT – passively – paracellular

route that is coupled to NaCl reabsorption• AL of Henles loop- 20% paracellular mechanism Requires a protein Paracellin-1 which is inhibited

by increased blood conc of Ca and Mg acting via CaSR expressed on BL membrane

Metabolism

Serum Calcium can be influenced by pH.

• Metabolic acidosis = decrease protein binding = increase ionized calcium.

•Metabolic alkalosis = increase protein binding = =decrease ionized calcium.

•Fall in pH by o.1 increases serum calcium by 0.1 mmol/L

•Corrected calcium• For every 1-g/dL drop in serum albumin

below 4 g/dL, measured serum calcium decreases by 0.8 mg/dL.

• Corrected calcium = Measured Ca + [0.8 x (4 - measured albumin)] (Calcium in mg/dl; albumin in g/dl)

FUNCTIONS of Calcium

•Normal cellular function & intracellular signalling

•Neuromuscular / nerve conduction•Cardiac contractility •Bone formation•Coagulation•Hormone & Enzyme regulation•Maintenance of plasma membrane stability.

Hormones in Calcium Homeostasis

18

CALCIUM, PTH, AND VITAMIN D FEEDBACK LOOPS

NORMAL BLOOD Ca

RISING BLOOD Ca

FALLING BLOOD Ca

SUPPRESS PTH

STIMULATE PTH

BONE RESORPTION

URINARY LOSS

1,25(OH)2 D PRODUCTION

BONE RESORPTION

URINARY LOSS

1,25(OH)2 D PRODUCTION

About Hypercalcaemia•Hypercalcaemia is one of the most

common biochemical abnormalities and is often detected during routine biochemical analysis in asymptomatic patients.

•Mild asymptomatic hypercalcaemia occurs in about 1 in 1000 of the population, with an incidence of 25–30 per 100000 population. It occurs mainly in elderly females, and is usually due to primary hyperparathyroidism.

•Mild hypercalcaemia (up to 11–11.5 mg/dL or <3 mmol/L) is usually asymptomatic and recognized only on routine calcium measurements)

•3.0 to 3.5 mmol/l may be well tolerated if it has risen slowly, but may be symptomatic and prompt treatment is usually indicated.

•Severe hypercalcaemia is defined as total serum calcium > 14 mg/dl (> 3.5 mmol/L). Risk of severe neurological symptoms or cardiac arrhythmias are present in such patient.

Evaluation Evaluation of a patient with hypercalcemia

should include a careful history and physical examination focusing on

• clinical manifestations of hypercalcemia,• risk factors for malignancy, •causative medications, •and a family history of hypercalcemia-

associated conditions

General Symptoms Of HypercalcaemiaRenal “stones”•Severe loin pain radiating to groin mimicking a

typical renal colic•Polyuria and polydipsia•Dehydration•Nephrocalcinosis

Skeleton “bones”•Bone pain•Arthritis•Osteoporosis and fractures•Osteitis fibrosa cystica in hyperparathyroidism

(sub-periosteal resorption, bone cysts)

Abdominal “groans”•Nausea, vomiting•Anorexia, weight loss•Constipation•Severe abdominal pain due to Pancreatitis

or Peptic ulcer diseasepsychic “moans”•Impaired concentration and memory•Confusion, stupor, coma•Lethargy and fatigue•Muscle weakness

Cardiovascular• Hypertension• Cardiac arrhythmias• Vascular calcification

Other• Itching• Redness of Eye and pain resembling

Conjunctivitis or Symptoms of Keratitis

Symptoms related to Underlying Etiologies•Commonest etiology in a patient with

hypercalcaemia being overactive parathyroid gland (specifically single parathyroid adenoma 80-90%). Initailly have milder or no symptoms. Later it’s characterized by

-hypercalcemia -PTH equal to or above the normal range -hypercalciuria -increased risk of fractures -increased risk of kidney stones -seldom causes extreme hypercalcemia unless confounded by renal failure, dehydration, etc.

•On the background of CKD, hypercalcaemia may favour tertiary hyperparathyroidism.

• A family history of such symptoms like renal stones may point towards FHH.

•Symptoms of abdominal pain, diarrhoea resembling Zollinger Ellison or features related to insulinoma, pituitary tumor, pheochromocytoma with family history point towards rare MEN I or II.

• Hypercalcaemia in malignancy (due to PTHrP over production in Solid Tumours, osteolytic metastasis in Ca breast or Myeloma, extra renal vit D activation)- Look for Squamous Cell Carcinoma lung, breast, renal, thyroid or Haematological malignancies (Leukaemia, lymphoma, Multiple myeloma). Rapidity of the course is the striking features here.

• Thiazide diuretics, excess vitamin D analogues, chronic lithium administration, vitamin A, teriparatide, theophylline intake or excess TPN must be searched as etiologies in patient with hypercalcaemia.

•Hypercalcaemia in patient with low grade fever evening rise, cough we must exclude tuberculosis.

•Hypercalcaemia patient having chest complains with fever, arthralgia, erythema nodosum or chest problems think of sarcoidosis.

•Patient working on mining, glass manufacturing factory with chest problem, hypercalcaemia might think of silicosis.

•Also HIV and leprosy must be ruled out.

• Features of Thyrotoxicosis, Acromegaly, Addison’s must be searched in continued mild hypercalcaemic patient.

• Patient taking high doses of calcium antacids might present hypercalcaemia in rare milk- alkali syndrome. The chronic form of the disease, termed Burnett’s syndrome which is associated with irreversible renal damage.

• Hypercalcaemia may be present in immobilized patient with high bone turnover (e.g., Paget’s disease, bedridden child)

•Hypercalcaemia in infant multiple congenital development defects, including supravalvular aortic stenosis, mental retardation, and an elfin facies may point towards Williams’ syndrome.

Signs•Mostly non-specific, may be related to

underlying disorders•Dehydration•Hypertension•Chondrocalcinosis may be due to ectopic

calcification• Corneal calcifcation or band keropathy

Band Keratopathy

Investigations•After ensuring baseline investigations CBC (anaemia

in myeloma, malignancy etc.), several fasting serum calcium and phosphate samples should be performed. Serum albumin must be measured to rule out pseudo-hypercalcaemia.

• Serum PTH: -The hallmark of primary hyperparathyroidism is ↑ Ca and ↓ PO4 with detectable or elevated intact PTH levels. Nothing is necessary if such patient asymptomatic except for excluding any drug history like lithium intake and FHH.

•24-hour urinary calcium or single calcium creatinine ratio (<0.01) effectively excludes familial hypocalciuric hypercalcaemia.

•Hyperchloraemic acidosis – often mild.•Renal function is usually normal except

for Tertiary hyperparathyroidism or multiple myeloma.

•Elevated serum alkaline phosphatase is found in severe parathyroid bone disease otherwise it suggests an alternative cause.

• Activated Vitamin D level >100 mg/ml may suggest vitamin D intake or granulomatous diseases

• PTH-related protein (PTHrP): High levels in a hypercalcaemic patient with ↓ PTH may suggest solid malignancies. So, if PTH levels are not elevated, then a thorough workup must be undertaken for malignancy, including Chest x-ray, CT of chest and abdomen & bone scan.

• Protein electrophoresis/immunofixation: to exclude myeloma

• Serum TSH: to exclude hyperthyroidism• 09:00 hours cortisol and/or ACTH test: to

exclude Addison’s disease• Serum ACE: helpful in the diagnosis of sarcoidosis

•Hydrocortisone suppression test: hydrocortisone 40 mg three times daily for 10 days leads to suppression of plasma calcium in sarcoidosis, vitamin D-mediated hypercalcaemia.

ECG in Hypercalcaemia

Short QT interval, Broad T, Heart Block will present. Rarely Osborn wave may be found.

Imaging: Chest X-ray

Pulmonary Tuberculosis SarcoidosisAlso used to detect any malignacy, hyperparathyroidism, paget’s etc.

Skull X-rayVery significant for Multiple myeloma, Primary hyperparathyroidism and Paget’s disease, acromegaly as a cause for patient with hypercalcaemia etc.

Imaging(contd.)•Abdominal X-rays may show renal

calculi or nephrocalcinosis. High-defnition hand X-rays can show subperiosteal erosions in the middle or terminal phalanges.

•DXA bone density scan: is useful to detect bone effects in asymptomatic people with hyperparathyroidism (HPT).

Parathyroid ImagingThe success of parathyroid imaging is frequently far less accurate than exploration. Methods include:

•Ultrasound which is insensitive for small tumours

•High-resolution CT scan or MRI (more sensitive)

•Radioisotope scanning using 99mTc-sestamibi, which is approximately 90% sensitive in detecting adenomas.

DDX Ca PO4 PTH PTHrP 1,25(OH)D U Ca

Malignancy↑ N/↑ ↓ ↑↑ ↓/N ↓/N

Primary PTH ↑ ↓ ↑ N ↑ ↑

Granulomatous disease

↑ ↑ ↓ N ↑↑ ↑

Vit D excess ↑ ↑ ↓ N ↑↑ ↑

Thiazide ↑/N ↑ ↓/N N N ↓

Milk alkali syndrome

↑/N ↑ ↓/N N N ↓

TreatmentAimed both at•Lowering the serum calcium if possible, •Treating the underlying disease. Main Principle of treatment aimed at reducing serum calcium by - 1. Inhibiting bone resorption 2. increasing urinary calcium excretion

or 3. decreasing intestinal calcium

absorption

•Patients with mild hypercalcaemia (<12 mg/dL) do not require immediate treatment. They should stop any medications, foods causing hypercalcaemia, avoid volume depletion and physical inactivity and maintain adequate hydration.

•Moderate Hypercalcaemia (12 to 14 mg/dL), especially if acute and symptomatic, requires more aggressive therapy.

•Severe hypercalcaemia (>14 mg/dL), even without symptoms, should be treated intensively.

•Treatment of underlying conditions.

Goals of Treatment

Management of Severe HypercalcaemiaAcute hypercalcaemia often presents with dehydration, nausea, vomiting, polyuria, drowsiness and altered consciousness. Urgent treatment is needed if the patient is seriously ill or if the Ca2+ is above 3.5 mmol/L (14 mg/dl).

Four basic principles to be followed-

1. Rehydration: At least 4–6 L of 0.9% normal saline on day 1 and 3–4 L for several days thereafter. Loop diuretics only used if fluid overload develops (not for reducing serum calcium). Need to consider hemodialysis with a low- or no-calcium dialysate if comatose, in severe renal failure, or cannot receive aggressive hydration.

2. Intravenous bisphosphonates: are the treatment of choice for hypercalcaemia as it inhibits osteoclastic bone resorption in malignancy or of undiagnosed cause. -Zoledronic acid (e.g., 4 mg over ∼30 min), -Pamidronate (e.g., 60–90 mg over 2–4 h), -Etidronate (e.g., 7.5 mg/kg per day for 3–7 consecutive days). Onset of action is within 1–3 days, with normalization occurs in 60–90% of patients.Repeated if relapse occurs.•Side Effect: Esophagitis, Osteonecrosis Of Jaw

3. Intravenous hydrocortisone (100–300 mg daily) or oral prednisone (40–60 mg daily): is effective in some instances (e.g. in myeloma, sarcoidosis and vitamin D excess) but in most cases is ineffective. Ketoconazole, chloroquine, and hydroxychloroquine may serve same purpose.

4. Calcitonin (200 units i.v. 6-hourly): Has a short-lived action and is little used. Can only be considered if poor response to bisphosphonates.Efficacy of calcitonin is limited to the first 48 hours.

Others• Calcimimetic agent (cinacalcet): Target

the calcium-sensing receptors (e.g. cinacalcet) used in parathyroid carcinoma and in dialysis patient and in primary hyperparathyroidism where surgical intervention is contraindicated.

• IV Phosphates- Chelates calcium & level. But, this therapy can be toxic because calcium-phosphate complexes may deposit in tissues and cause extensive organ damage.

• Gallium nitrate

Treatment of Underlying Conditions1. Primary hyperparathyroidismPatients who are treated conservatively without surgery should have calcium biochemistry and renal function checked annually and bone density monitored periodically.

Medical management in milder cases• No effective medical therapies • A high fluid intake should be maintained • A high calcium or vitamin D intake avoided and

exercise encouraged

Surgical management• Asymptomatic patients with significant

hypercalcaemia (corrected serum calcium > 2.85 mmol/L (> 11.4 mg/dL)

• Individuals aged less than 50 years with symptoms or complications (such as peptic ulceration, renal stones, renal impairment or osteoporosis/Low bone mineral density(T-score ≤2.5) at any site.

Side Effects: • Postoperative hypocalcaemia• Bleeding and recurrent laryngeal nerve palsies

(<1%). (Vocal cord function should be checked preoperatively)

2. Familial hypocalciuric hypercalcemia• Differentiation must be needed from

Primary PTH because surgery is not all necessary here (except for rare consanguineous marriages of a homozygous or compound heterozygote state, resulting in severe impairment of calcium-

sensing receptor function neonatal severe hypercalcemia, total parathyroidectomy is mandatory.)

3. Malignancy-Associated Hypercalcaemia :•Control of tumor should be considered best

management as reduction of tumor mass usually corrects hypercalcaemia.

•Intravenous bisphosphonates: For acute management as well as maintenance.

4. Excessive Vit D Production related causes:•Restriction of dietary calcium intake or Vit D

intake•Glucocorticoids: 100 mg/d of hydrocortisone.•Treatment of specific disease (TB etc.)

5. Withdrawal of offending drugs (lithium) if present considering the risk- benefit ratio. 6. Treatment of other disorders especially endocrinopathies: Patients with thyrotoxicosis, addison’s, acromegaly, pheochromocytoma should be treated accordingly.

Conclusion•The diagnostic approach to hypercalcaemia

often is made incidentally in asymptomatic patients but that does not mean to take it lightly.

•Hypercalcaemia do serve as a harbinger of light to severe underlying disease. Significant occult malignancies may present with hypercalcaemia for one just month.

•So, a proper clinical attitude must be served to all the suspect patients accordingly. We must ‘hit early’ & ‘hit good.’